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Review

Stem Cell Transplantation for Peripheral Nerve Regeneration: Current Options and Opportunities

by
Liangfu Jiang
1,
Salazar Jones
2 and
Xiaofeng Jia
1,2,3,4,5,6,*
1
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, China
2
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
3
Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
4
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
5
Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
6
Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2017, 18(1), 94; https://doi.org/10.3390/ijms18010094
Submission received: 15 December 2016 / Revised: 26 December 2016 / Accepted: 27 December 2016 / Published: 5 January 2017
(This article belongs to the Special Issue Peripheral Nerve Regeneration: From Bench to Bedside)
Browse Figure
Versions Notes

Abstract

:
Peripheral nerve regeneration is a complicated process highlighted by Wallerian degeneration, axonal sprouting, and remyelination. Schwann cells play an integral role in multiple facets of nerve regeneration but obtaining Schwann cells for cell-based therapy is limited by the invasive nature of harvesting and donor site morbidity. Stem cell transplantation for peripheral nerve regeneration offers an alternative cell-based therapy with several regenerative benefits. Stem cells have the potential to differentiate into Schwann-like cells that recruit macrophages for removal of cellular debris. They also can secrete neurotrophic factors to promote axonal growth, and remyelination. Currently, various types of stem cell sources are being investigated for their application to peripheral nerve regeneration. This review highlights studies involving the stem cell types, the mechanisms of their action, methods of delivery to the injury site, and relevant pre-clinical or clinical data. The purpose of this article is to review the current point of view on the application of stem cell based strategy for peripheral nerve regeneration.

1. Introduction

Peripheral nerve injuries (PNI) are mainly related to trauma, tumor, and iatrogenic lesions, leading to neurologic deficits and functional disability. The incidence of PNI is estimated at about 18 per 100,000 persons every year in developed countries, whereas it is relatively higher in developing countries [1,2].
Primary repair with suture is the preferred management for nerve discontinuities without a gap. Despite an excellent tension-free nerve repair, the functional outcome can be limited by inflammation, scar formation, and misdirection of regenerating sensory and motor axons. Regeneration is still subject to a rate of approximately 1 mm/day [3]. For nerve discontinuities with a gap, nerve autografts are useful but limited by availability and donor site morbidity. The various synthetic conduits and acellular allografts on the market, which we have previously reviewed, are not generally recommended for gaps >3 cm [4]. Although advanced bioengineering can recreate the nerve extracellular matrix, nerve conduits lack the critical cellular component, specifically Schwann cells (SC) critical for regeneration. SCs, by secreting various neurotrophic and neurotropic factors, develop a microenvironment conducive to axonal regeneration [5]. SCs interact with the surrounding extracellular matrix to stabilize myelin in the normal state, and can switch to a pro-myelination phenotype during regeneration [6].
Multiple neurotrophic factors including nerve growth factor (NGF) and glial-cell-derived neurotrophic factors (GDNFs) are stimulated by nerve injury and accelerate axon growth [7]. However, mature SCs in peripheral nerve do not maintain a growth-permissive phenotype to support axonal regeneration. Moreover, the requirement of sufficient SCs within a short time seriously limits its clinical application [8]. Stem cells are of interest as a source of Schwann-like cells that would take residence in the nerve and support a stable pro-regeneration environment.
The aim of this article is to discuss the features of different types of stem cells relevant to peripheral nerve regeneration, their mechanism of benefits, cell delivery, and relevant pre-clinical or clinical data of each.

2. Stem Cell Sources

Stem cells refer to cells that possess the capability of self-renewal in addition to differentiation to a more specialized cell type [1]. According to the development stage, stem cells can be divided into embryonic stem cells and adult stem cells. Stem cells can be characterized by their differentiation potential. Totipotent stem cells can form an entire embryo including the extraembryonic tissues. Pluripotent stem cells can trigger the mesoderm, endoderm, and ectoderm. Postnatal or adult stem cells are capable of multi-lineage differentiation in cells of only one germ layer. Unipotent or progenitor stem cells can only differentiate into one defined cell type [2]. The differentiation potential of stem cells can be related to their developmental stage. Differentiation potential decreases from an embryonic stem cell to a specialized tissue stem cell. Fully differentiated adult somatic cells do not naturally have any differentiation potential. Induced pluripotent stem cells (iPSC) are a type of pluripotent stem cell that can be generated directly from adult cells [3]. Thomson et al. showed that somatic cells could be transcriptionally regulated to express a more embryonic phenotype, thus creating the first induced pluripotent stem cells (iPSC) [1].
This review evaluates different types of stem cells based on development stage including iPSC and tissue source.

2.1. Embryonic Stem Cells (ESCs)

ESCs are pluripotent stem cells derived from the blastocyst stage of embryonic development [4]. ESCs can differentiate into somatic cells from all three embryonic germ layers. Several strategies with ESCs have been employed in the area of peripheral nerve injuries.
To replace the necessary Schwann cells needed for nerve regeneration, Ziegler et al. developed a protocol to generate Schwann cells from human ESCs with 60% efficiency [5]. The differentiated Schwann cells were shown to associate with axons. In a rat sciatic nerve injury model Cui et al. achieved significantly improved regeneration by the microinjection of neutrally-induced ESCs [6]. Immunostaining demonstrated that the ESCs survived and had differentiated into Schwann-like cells [6]. An alternative strategy is to inject the ESCs into the target muscle at the time of nerve injury/repair to prevent muscle denervation changes and slightly speed recovery [7].
ESCs are also of interest for the generation of additional stem cell lines. Adult stem cell lines typically require an invasive procedure for harvesting and can be limited by the quantity obtained. Mesenchymal stem cells (MSCs) can be generated from ESCs and have been used in pre-clinical animal models [8,9].
ESCs have great potential, but are not without their disadvantages. ESCs have the potential for teratoma formation [4]. In addition, there are limited sources of human embryos from which ESCs are obtained. There also exists the ethical dilemma of using a human embryo which contains the potential to form a complete individual for research or clinical applications.

2.2. Neural Stem Cells (NSCs)

NSCs are stem cells capable of differentiating into neurons or glial cells. They are present during neurogenesis for the proper organization of the brain and spinal cord. NSCs have been isolated from murine models and proliferated in vitro [10,11]. In the adult human brain, NSCs take residence in the subventricular zone and hippocampus [12,13]. Adult NSCs are thought to have a limited role in central nervous system injury [14]. In 1992, two groups reported the successful isolation of NSCs from the brain tissue of adult mice [10,11]. A variety of studies have demonstrated that NSC implantation is beneficial in both acute and chronic PNI [15,16]. However, NSCs have several disadvantages and limitations. Commercial murine C17.2 NSCs showed a high rate of neuroblastoma formation in an animal model [17]. Despite NSCs being discovered in multiple areas in the brain, they are difficult to harvest from the brain [18]. In addition, directed differentiation of specialized neural cell lines is difficult and the current methods are only effective in limited cases [19].

2.2.1. Mesenchymal Stem Cells (MSCs)

Though initially identified as a multipotent fibroblastic cell population within bone marrow different from a hematopoietic lineage [20], MSCs can be obtained from a wide range of non-marrow sources. MSCs have been isolated from adipose tissue, peripheral blood, amniotic fluid, umbilical cord, tendon and ligaments, hair follicle, synovial membranes, olfactory mucosa, dental pulp, and fetal tissue [21]. MSCs are of considerable interest in tissue regeneration given their differentiation potential, easy isolation, and immunomodulation [22]. MSCs are inherently capable of differentiating into all mesoderm lineages: fat, bone, muscle, and cartilage [22]. Under the proper environment, MSCs differentiation can be guided into non-mesenchymal lineages, such as neurons, astrocytes, and Schwann-like cells [23] to support nerve regeneration. The sub-types of MSCs based on tissue source and related application in PNI are discussed.

Bone Marrow-Derived Stem Cells (BMSCs)

BMSCs can differentiate into neurons, astrocytes, and SC-like cells under suitable conditions [23]. The fate of the BMSCs may be dictated by post transplantation physiological microenvironment. Almost 5% of BMSCs were induced to differentiate into Schwann cells within the lesioned nerve tissue 33 days after transplantation [24]. Nijhuis et al. showed that BMSCs implanted within a muscle in vein autograft led to an early increase in nerve growth factor and S100 positive Schwann-like cells compared to muscle in vein autograft alone in a rat sciatic nerve injury model [25]. Wang et al. demonstrated superior recovery with BMSCs suspended in matrix compared to autologous nerve graft in a 10-mm rabbit sciatic nerve injury model [26]. Rabbits with BMSCs suspended in matrix had significantly greater motor nerve conduction velocities and amplitudes [26]. Interestingly, the regenerative benefits of BMSCs plated onto poly-caprolactone filaments were superior to exogenous Schwann cells plated onto filaments in a rat model [27]. Raheja et al. showed that BMSCs improve in a dose-dependent manner the extent of myelination, thickness of myelin, and axonal thickness in a rat model [28]. There is no clinical data regarding the beneficial effects of BMSC transplantation for nerve regeneration, however, it has already been clinically used to treat myocardial infarction [29,30] and spinal cord injury [31].
Although BMSCs present more easily harvested than ESCs and NSCs, the capacity of proliferation and differentiation of BMSCs is inferior to the latter. In addition, BMSCs are limited by the need for an invasive procedure for autologous harvesting. The procurement procedures are invasive and painful that usually need anesthesia, whereas the obtained stem cell fraction is obviously lower than from other sources.

Adipose-Derived Stem Cells (ADSCs)

ADSCs can be derived from adipose tissue obtained from common procedures such as liposuction. These cells are particularly advantageous since they are available via minimally invasive harvesting with a high cellular yield of (0.25−0.375) × 106 cells per milliliter of liquid fat after 4 to 6 days in culture with medium containing 10% fetal bovine serum [32]. They show higher proportion and superior proliferation and differentiation potential compared with BMSCs [33]. ADSCs can be differentiated into an SC-like phenotype (differentiated adipose-derived stem cell, dASC) which shares morphological and functional properties with SC, thus representing a valid SC alternative [34,35,36,37]. Several studies have indicated there were no significant difference for sciatic nerve regeneration by using 2- or 14-day dASCs [38,39]. Liu et al. cut rat sciatic nerves into 1-cm fragments, and then soaked them in a filtered differentiation-inducing culture medium for two days. Differentiated rat ADSCs were similar to genuine Schwann cells after being incubated with the above induction medium for five days. The vast majority of studies show an augmented effect of ADSCs seeded in silicone conduits on peripheral nerve regeneration [40,41]. Particularly, ADSC transplantation decreases muscular atrophy, facilitates sorting of axons and myelination, and reduces inflammation [42,43]. Some investigators consider ADSCs to have a similar therapeutic effect compared with autologous SCs and BMSCs [44]. Rather than differentiate to SC phenotype, it is hypothesized that ADSCs mainly facilitate endogenous SC recruitment by releasing growth factors such as NGF, vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF) [39,45,46] for nerve protection and regeneration, as the therapeutic effect is maintained for several weeks even after many ADSCs are gone [47]. ADSCs may aid angiogenesis both by direct differentiation into vascular endothelium, and their associated paracrine effects [48,49]. Like BMSCs, the neurotrophic potential of ADSCs is influenced by the harvest site [50], fat layer [51], and donor age [46]. Another restriction is the differentiation potential towards adipocytes, which is unfavorable for nerve regeneration [52]. Accessible harvest and better stem cell characteristics make ADSCs one of the optimal choices for pre-clinical studies.

2.2.2. Fetal-Derived Stem Cells

Fetal tissues are the most primitive source of MSCs and have received less genetic damage caused by age, environment, and disease [53]. Stem cells can be derived from multiple sources, such as amniotic fluid, amniotic membrane, umbilical cord, and Wharton’s jelly. Since such tissues are generally abandoned after birth, fetal-derived stem cells are in sufficient excess and can be easily obtained without the need for invasive procedures. The cells obtained can proliferate in culture and differentiate into a neural phenotype [54].

Amniotic Tissue-Derived Stem Cells (ATDSCs)

ATDSCs are derived from amniotic fluid or the amniotic membrane. ATDSCs possess the characteristics of both mesenchymal and NSCs [55] and can differentiate into neural tissue [56]. They also exhibit strong angiogenic potential, as their implantation augmented blood perfusion and enhanced intraneural vascularity in addition to promote peripheral nerve regeneration [57,58]. Survival of ATDSCs following transplantation is a challenge to their clinical application. Genetic modification and inhibition of inflammatory mediators can restrain the apoptotic cascade [59]. Several reports have explored the effect of gene mutation in ATDSCs on PNI. Human ATDSCs with GDNF modification significantly enhance viability, regeneration, and motor function in animal models [60]. Stromal cell-derived factor-1α (SDF-1α) expression in muscle and nerve after PNI can recruit ATDSCs for their deposition, thus in time, ATDSC injection at high levels of SDF-1α effectively increases the number of ATDSCs at the repair site, promoting nerve regeneration [61].

Umbilical Cord-Derived MSCs (UC-MSCs)

UC-MSCs are a promising candidate for cell therapies because of their differentiation and proliferation potential. They are easily accessible from the postnatal tissue that is discarded after birth, thus facing fewer ethical problems. Though UC-MSCs have the proliferative ability, there are few reports about the tumorigenesis of UC-MSCs or UC-MSC-derived cells in transplantation experiments [62]. Matsuse et al. reported a system to induce UC-MSCs to differentiate into cells with SC properties using β-mercaptoethanol followed by retinoic acid and a set of specific cytokines [63]. Further investigation revealed that Schwann-like cells differentiated from UC-MSCs generated neurotrophic factors like NGF and BDNF [64]. In addition, the differentiated human Schwann-like cells transplanted into rat transected sciatic nerve under immunosuppression maintained the differentiated phenotype, elicited axonal regeneration from the proximal segment, and constructed peripheral nerve system (PNS) tissue. This was even functionally equivalent to authentic SCs based on walking track analysis [65]. This indicates that UC-MSCs could be used to alternatively generate Schwann-like cells for PNI regenerative therapy.

Wharton’s Jelly MSCs (WJMSCs)

Wharton’s jelly is a special primitive connective tissue protecting vessels in the umbilical cord [66]. Cells in its stromal compartment show specific mesenchymal features, thus named Wharton’s jelly MSCs (WJMSCs) [67]. WJMSCs have shown the capacity to differentiate to Schwann-like cells. Furthermore, they can generate neurotrophic factors including NGF, BDNF, and neurotrophin-3 (NT-3), and trigger axon growth in vitro [68]. Thus, Wharton’s jelly can become an ideal source of MSCs, characterized as unique and easily accessible.
Fetal tissue provides a prospective alternative for stem cells acquisition. The main obstacles of their application, alloreactivity and immunoreactivity, may not be encountered in stem cells from other sources. Cell bank for the storage of fetal products provides a resolution for this conundrum.

2.2.3. Skin-Derived Precursor Stem Cells (SKP-SCs)

SKP-SCs located in the dermis are an available source for somatic multipotent cells. In addition to durable proliferative ability, SKP-SCs can differentiate to a diverse array of cell types, including melanocytes, craniofacial cartilage, bone, connective tissue, vascular smooth muscle, endocrine cells, neurons, and glial cells [69]. SKP-SCs cultured in neuregulin-1β express the same markers with SCs [70]. Moreover, both undifferentiated and differentiated SKP-SCs have exhibited acceleration on nerve regeneration. SKP-SCs treatment significantly increases mean axon counts and reduces the percentage of myelin debris [71]. Several studies demonstrated the superior outcomes of SKP-SCs on de-myelination and crush injury [70,72], and acute and chronic transection injury [71].

2.2.4. Hair Follicle Stem Cells (HFSCs)

Hair follicle stem cells are embryologically from the neural crest, and are an abundant and accessible source for pluripotent stem cells [73]. HFSCs are readily expanded in culture but cannot be kept for long periods, which is similar to SKP-SCs. ESC transcription factors Nanog, Oct4, and nestin are positively expressed in HFSCs. Furthermore, HFSCs also can differentiate to a variety of cell types, such as adipocytes, smooth muscle cells, melanocytes, neurons, and glial cells [74]. One of the advantages of HFSCs is that they can differentiate into pure human SC population rapidly in a straightforward way, without the requirement of genetic manipulation. Undifferentiated HFSCs used in a murine model with sciatic and tibial nerve crush and transection injuries demonstrated significantly improved function [75]. Improved outcomes in 4-cm rat sciatic nerve defects were seen by the addition of neurons and Schwann cells derived from HFSCs to an acellular xenograft [76].

2.2.5. Dental Pulp Stem Cells (DPSCs)

New odontoblast formation and dentin production in response to severe tooth damage suggested the existence of MSCs in dental pulp tissue. DPSCs were first isolated in 2000 and found to differentiate into odontoblast-like cells [77]. They also exhibit the feature of MSCs that can be induced into multi-lineage including neural cells under appropriate culture condition. Specifically, DPSCs can express neural markers, generate neurotrophic factors, promote axon guidance, and differentiate into functionally active neurons [78]. Although available data is limited, DPSCs have been shown to chemoattract trigeminal ganglion axons [79], differentiate into SCs or nourish SC to support dorsal root ganglion neurite outgrowth, and guide myelin repair [80,81]. DPSCs secrete various trophic factors that enhance peripheral nerve regeneration [82]. Moreover, DPSCs are reported to have a stronger proliferation and greater clonogenic potential, and a larger stem/progenitor cell population in comparison to BMSCs [83], suggesting their clinical applicability. Moreover, they were reported to improve function through combination with a pulsed electromagnetic field in the form of SC-like cells [84]. In a manner similar to fetal tissue, autologous cells can be easily harvested but require storage [82]. Cell banking should thus be considered due to the properties of easy isolation and cryopreservation.

2.2.6. Muscle-Derived Stem/Progenitor Cells (MDSPCs)

MDSPCs can be derived from skeletal muscle and have sustained self-renewal, long-term proliferation, and multipotent differentiation [85,86]. Although MDSPCs have shown potential for regeneration of skeletal and cardiac muscles, bone, and articular cartilage, there is limited research about their role in human nerve repair. Some researchers reported that MDSPC transplantation could be applied for neuropathy as they can differentiate into SCs, perineurial/endoneurial cells, vascular endothelial cells, and pericytes needed for neurovascular regeneration [87,88]. Peripheral nerve damage frequently accompanies musculoskeletal trauma. MDPCs from traumatized muscle tissue secrete the neurotrophic factors that are associated with muscle tissue reinnervation [89].Though MDSPCs present an opportunity in peripheral nerve regeneration together with muscle atrophy prevention, limited evidence and the appropriate harvest site are still challenges in the current stage.

2.3. Induced Pluripotential Stem Cells (iPSCs)

Considering the limitation of various types of stem cells, researchers tried to artificially induce the stem cells. Takahashi demonstrated a protocol of defined transcription factors to induce pluripotency in mouse and human fibroblasts [3]. The ability of reprograming cells supplies new hope to develop an individual-specific pluripotent stem cell that can overcome the restriction of ESCs. At present, understanding of iPSCs has advanced in multiple disease mechanisms and they are used for in vitro drug screening and therapeutic efficacy evaluation [90]. In addition to differentiation into somatic cells, the method of inducing iPSCs differentiation along neural lineages has been established [91]. In spite of subdued efficiency and enhanced variability during the differentiation process [92], iPSCs have presented a regenerative potential in animal models of central and peripheral nerve injury [93].
iPSCs have been used to induce neurospheres in 3-D-culture to maintain the ability to form neural or glia cells [94]. iPSCs have been applied to coat a tissue-engineered bioabsorbable nerve conduit and implanted to PNI mice. Axonal regeneration and myelination were enhanced without teratoma formation following 48-week observation, suggesting their alternative application potential in PNI [95].
Though iPSCs are favorable over ESC given the avoidance of ethical issues and need for immunosuppression, there exists still for iPSCs in clinical applications such as epigenetic memory from the original somatic cells, chromosomal aberrations, and tumorigenicity [96].
The comparison of stem cells from different resources is listed in Table 1. For the clinical application of stem cell-based transplantation, the ideal source should be individualized, immune tolerant, easy to harvest, non-tumorigenic, able to be integrated in the host nerve tissue, and efficient in replacement.

3. Mechanism of Action

The impact of stem cells transplantation in PNI mainly depends on their capacity in differentiation phenotype, ability in enhancing neurotrophic action, and promotion of myelin formation (Figure 1).

3.1. Differentiation Type of Stem Cells

The self-renewal capacity of stem cells makes it possible to deliver numerous cleavage cells to the damage site [23]. The stem cells continue proliferating after migrating to the injured nerve tissue, and further differentiate to the necessary cell type under the appropriate microenvironmental conditions [97]. It is confirmed that NSCs can be induced to a peripheral neuron, SC, or smooth muscle phenotype upon co-culture with cells from the nervous system. Furthermore, about 5% of BMSCs can spontaneously transdifferentiate into SCs without specific intervention [24]. However, the differentiation rate of naive precursor cells in the peripheral nerve is relatively low [58]. Predifferentiating stem cells toward a desired phenotype in vitro by chemical induction, biological treatment, gene transfection, or co-culture with neural cells before injection is an effective method. The representative protocol of MSC induction is exposure to or transfection by growth factors β-mercaptoethanol (β-ME) and alltransretinoic acid (RA), the cytokines forskolin (FSK), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF) sequentially [98]. In particular, BMSCs can express NSC markers by transfecting the transmembrane region and intracellular domain of notch [99] or differentiating into neurosphere cells upon Noggin transfection [100]. Stem cells were maintained in differentiation medium for 2 weeks in most protocols [101,102]. This is time consuming. Finally, SC-like cells must be co-cultured with dorsal root ganglion neurons to maintain stable morphological features upon juxtacrine neuronal cues [103].
With predifferentiation, SC markers are increased and maintained for longer time upon treatment before delivery [70]. After differentiated stem cell transplantation, accelerated transected axons regenerate and achieve better remyelinization [104]. The extent of recovery was comparable to or even greater than that observed after Schwann cell transplantation [105]. Other experiments showed primary Schwann cells were significantly improved with respect to distal stump sprouting compared to differentiated bone marrow-derived mesenchymal stem cells (dMSC) and dASC-loaded conduits [106]. In contrast, some scholars reported that predifferentiation facilitates post-transplant cell death, which may be caused by enhanced ability of major histocompatibility complex antigens or reduced proliferation ability compared with naïve stem cells [107]. Another potential drawback of MSCs is the tumorigenic capability, as shown by the high rate of tumorigenesis observed in rat sciatic nerve injury model transplanted by C17.2 neural stem cells [17].

3.2. Neurotrophic Action Enhancement

Other than differentiation to appropriate cells, stem cells also provide a beneficial microenvironment for neural cell survival and neurogenesis by secreting bioactive neurotrophic molecules [46,108]. In addition to support SC differentiation, maturation, and proliferation, stem cells may exhibit better performance in enhancing neurotrophic action. MSCs synthesize and release a variety of growth factors, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), GDNF, neurotrophin-3 (NT-3), VEGF, and ciliary-derived neurotrophic factor (CDNF) [109]. SKP-SCs increase BDNF, NGF, and NT-3 compared with single SCs in culture [108]. ADSCs also upregulate protein expression of BDNF, glial growth factor, neuregulin-1, VEGF, HGF, and insulin-like growth factor [46]. Furthermore, overexpressed neurotrophic factors facilitate the regeneration of peripheral nerves even beyond the nerve injured region. ADSCs may alleviate dorsal root ganglion loss upon inhibiting caspase-3 activity in a neurotrophin-dependent manner [110].
The level of growth factors in the microenvironment also affects the influence of transplanted stem cells for feedback. NGF neutralizing antibody can abrogate the stimulatory effect of BMSCs on neurite growth of sensory and sympathetic neurons in vitro [111]. BDNF neutralizing antibody reduces the influence of ADSCs on nerve sprouts growth in vivo [112].

3.3. Myelin Promotion

Myelination is another major factor that determines the regeneration quality and functional recovery in PNI. Multiple types of somatic stems cells present the ability to myelinate neuronal cells in the form of SC-like cells in vitro [113]. SCs play a critical role for myelin sheath structure and function recover by synthesizing a large amount of myelin proteins, such as myelin basic protein (MBP), P0, and PMP22 [114]. Similar to SCs, stem cells differentiated into SC-like cells also show the capacity of supporting myelination in regenerated nerves in vivo [113]. A study SC-like BMSCs injected to the autologous vein conduits significantly increase the number of myelinated axons and improve the facial nerve functional recovery through enhancing myelin factors mRNA expression [104]. Transplantation of gingiva-derived mesenchymal stem cells (GMSCs) and induced neural progenitor cells (iNPCs) promotes peripheral nerve repair/regeneration, possibly by promoting remyelination of Schwann cells mediated via the regulation of the antagonistic myelination regulators, c-Jun and Krox-20/EGR2 [115].

4. Stem Cell Delivery

Stem cells can be delivered through numerous ways (Table 2). The stem cells can be suspended in a medium that can be directly microinjected into the nerve ending [116]. The process of microinjection can be traumatic both to the stem cells and delicate intra-neural architecture, leading to abnormal cell distribution. Another method is to suspend the stem cells in fibrin matrix and inject the matrix around the repair sites [26,117]. In repairs with a conduit, stem cells can be injected in the conduit lumen or on the conduit matrix. Tse et al. describes a method for inkjet printing Schwann cells with phenotypic analysis over seven days. Glial cell viabilities of >90% were detected immediately after printing [118]. Three-dimensional printing [119,120] aims at creating tissues with multiple cell types within a scaffold for mimicking native tissue, which is a progressive step towards peripheral nerve printing. Further refinement of the delivery system may provide better cell distribution and improve efficacy. Three-dimensional printing technology for fabricating can provide the desired geometry, such as multichannel, bifurcating and personalized structures, which allows the customization of a nerve guidance conduit (NGC) that precisely matches a particular nerve defect of a patient [121,122].
Natural conduits such as vein and artery grafts are abundant in extracellular matrix (ECM) proteins such as collagen and laminin, thus contributing to cell adhesion and axonal guidance [25]. Commercially natural conduits are usually filled with ECM components including collagen [126] and fibrin [127]. Artificial conduits are mainly synthetized by polyglycolic acid [123], silk fibroin [124], poly-epsilon-caprolactone [27], polyhydroxybutyrate [130], silicone tube [131], polytetrafluoroethylene [125], or chitosan [128]. Recently, biological and nanofibrous conduits have rapidly developed, while the concern for their application in cell therapy include degradation waste and velocity [132]. Natural materials are prone to degrade in a non-toxic manner, and the velocity might be too fast. In contrast, part of synthetic polymers can produce acidic materials during degradation which is detrimental to the microenvironment and cellular activity [133]. The internal structure within the basal lamina is beneficial for axonal guidance compared with hollow lumen tubes, which are composed of organized multiple fibers [128,129] or less orderly collagen sponges [125].

5. Perspective

Peripheral nerve regeneration is a dynamic process. Stem cell transplantation still remains in the pre-clinical stage and has yet to make significant headways into clinical practice. In spite of genetic manipulation, cell instability, and tumorigenesis, stem cell homing and migration remains a concern. Simple application of stem cell transplantation has shown some improvements in outcomes, but is still inferior to nerve repair with conventional techniques. Pre-clinical and eventually clinical studies comparing different types of stem cell are needed. Other factors such as optimal Schwann cell differentiation, exact underlying mechanisms of action, and cell delivery have yet to be solidified, making it difficult to draw clear conclusions. Cell banks may provide benefits for future applications of stem cell therapy.

Acknowledgments

The work was supported by Maryland Stem Cell Research Fund (2013-MSCRFE-146-00) (to Xiaofeng Jia), and R01HL118084 from NIH (to Xiaofeng Jia).

Author Contributions

Liangfu Jiang searched and reviewed literature, drafted manuscript and revision; Salazar Jones drafted and revised the manuscript; Xiaofeng Jia designed and formulated the review theme, viewed the literature, revised and finalized the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Thomson, J.A.; Itskovitz-Eldor, J.; Shapiro, S.S.; Waknitz, M.A.; Swiergiel, J.J.; Marshall, V.S.; Jones, J.M. Embryonic stem cell lines derived from human blastocysts. Science 1998, 282, 1145–1147. [Google Scholar] [CrossRef] [PubMed]
  2. Martens, W.; Bronckaers, A.; Politis, C.; Jacobs, R.; Lambrichts, I. Dental stem cells and their promising role in neural regeneration: An update. Clin. Oral Investig. 2013, 17, 1969–1983. [Google Scholar] [CrossRef] [PubMed]
  3. Takahashi, K.; Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006, 126, 663–676. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Rippon, H.J.; Bishop, A.E. Embryonic stem cells. Cell Prolif. 2004, 37, 23–34. [Google Scholar] [CrossRef] [PubMed]
  5. Ziegler, L.; Grigoryan, S.; Yang, I.H.; Thakor, N.V.; Goldstein, R.S. Efficient generation of schwann cells from human embryonic stem cell-derived neurospheres. Stem Cell Rev. Rep. 2011, 7, 394–403. [Google Scholar] [CrossRef] [PubMed]
  6. Cui, L.; Jiang, J.; Wei, L.; Zhou, X.; Fraser, J.L.; Snider, B.J.; Yu, S.P. Transplantation of embryonic stem cells improves nerve repair and functional recovery after severe sciatic nerve axotomy in rats. Stem Cells 2008, 26, 1356–1365. [Google Scholar] [CrossRef] [PubMed]
  7. Kubo, T.; Randolph, M.A.; Groger, A.; Winograd, J.M. Embryonic stem cell-derived motor neurons form neuromuscular junctions in vitro and enhance motor functional recovery in vivo. Plast. Reconstr. Surg. 2009, 123, 139S–148S. [Google Scholar] [CrossRef] [PubMed]
  8. Lian, Q.; Lye, E.; Suan Yeo, K.; Khia Way Tan, E.; Salto-Tellez, M.; Liu, T.M.; Palanisamy, N.; El Oakley, R.M.; Lee, E.H.; Lim, B.; et al. Derivation of clinically compliant MSCs from CD105+, CD24− differentiated human ESCs. Stem Cells 2007, 25, 425–436. [Google Scholar] [CrossRef] [PubMed]
  9. Lee, E.J.; Xu, L.; Kim, G.H.; Kang, S.K.; Lee, S.W.; Park, S.H.; Kim, S.; Choi, T.H.; Kim, H.S. Regeneration of peripheral nerves by transplanted sphere of human mesenchymal stem cells derived from embryonic stem cells. Biomaterials 2012, 33, 7039–7046. [Google Scholar] [CrossRef] [PubMed]
  10. Reynolds, B.A.; Tetzlaff, W.; Weiss, S. A multipotent egf-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J. Neurosci. 1992, 12, 4565–4574. [Google Scholar] [PubMed]
  11. Snyder, E.Y.; Deitcher, D.L.; Walsh, C.; Arnold-Aldea, S.; Hartwieg, E.A.; Cepko, C.L. Multipotent neural cell lines can engraft and participate in development of mouse cerebellum. Cell 1992, 68, 33–51. [Google Scholar] [CrossRef]
  12. Paspala, S.A.; Murthy, T.V.; Mahaboob, V.S.; Habeeb, M.A. Pluripotent stem cells—A review of the current status in neural regeneration. Neurol. India 2011, 59, 558–565. [Google Scholar] [CrossRef] [PubMed]
  13. Goncalves, J.T.; Schafer, S.T.; Gage, F.H. Adult neurogenesis in the hippocampus: From stem cells to behavior. Cell 2016, 167, 897–914. [Google Scholar] [CrossRef] [PubMed]
  14. Cao, Q.; Benton, R.L.; Whittemore, S.R. Stem cell repair of central nervous system injury. J. Neurosci. Res. 2002, 68, 501–510. [Google Scholar] [CrossRef] [PubMed]
  15. Heine, W.; Conant, K.; Griffin, J.W.; Hoke, A. Transplanted neural stem cells promote axonal regeneration through chronically denervated peripheral nerves. Exp. Neurol. 2004, 189, 231–240. [Google Scholar] [CrossRef] [PubMed]
  16. Lee, D.C.; Chen, J.H.; Hsu, T.Y.; Chang, L.H.; Chang, H.; Chi, Y.H.; Chiu, I.M. Neural stem cells promote nerve regeneration through IL12-induced schwann cell differentiation. Mol. Cell. Neurosci. 2016. [Google Scholar] [CrossRef] [PubMed]
  17. Johnson, T.S.; O’Neill, A.C.; Motarjem, P.M.; Nazzal, J.; Randolph, M.; Winograd, J.M. Tumor formation following murine neural precursor cell transplantation in a rat peripheral nerve injury model. J. Reconstr. Microsurg. 2008, 24, 545–550. [Google Scholar] [CrossRef] [PubMed]
  18. Ernst, A.; Alkass, K.; Bernard, S.; Salehpour, M.; Perl, S.; Tisdale, J.; Possnert, G.; Druid, H.; Frisen, J. Neurogenesis in the striatum of the adult human brain. Cell 2014, 156, 1072–1083. [Google Scholar] [CrossRef] [PubMed]
  19. Zhang, H.; Wei, Y.T.; Tsang, K.S.; Sun, C.R.; Li, J.; Huang, H.; Cui, F.Z.; An, Y.H. Implantation of neural stem cells embedded in hyaluronic acid and collagen composite conduit promotes regeneration in a rabbit facial nerve injury model. J. Transl. Med. 2008, 6, 67. [Google Scholar] [CrossRef] [PubMed]
  20. Friedenstein, A.J.; Gorskaja, J.F.; Kulagina, N.N. Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp. Hematol. 1976, 4, 267–274. [Google Scholar] [PubMed]
  21. Maltman, D.J.; Hardy, S.A.; Przyborski, S.A. Role of mesenchymal stem cells in neurogenesis and nervous system repair. Neurochem. Int. 2011, 59, 347–356. [Google Scholar] [CrossRef] [PubMed]
  22. Pittenger, M.F.; Mackay, A.M.; Beck, S.C.; Jaiswal, R.K.; Douglas, R.; Mosca, J.D.; Moorman, M.A.; Simonetti, D.W.; Craig, S.; Marshak, D.R. Multilineage potential of adult human mesenchymal stem cells. Science 1999, 284, 143–147. [Google Scholar] [CrossRef] [PubMed]
  23. Tohill, M.; Terenghi, G. Stem-cell plasticity and therapy for injuries of the peripheral nervous system. Biotechnol. Appl. Biochem. 2004, 40, 17–24. [Google Scholar] [PubMed]
  24. Cuevas, P.; Carceller, F.; Dujovny, M.; Garcia-Gomez, I.; Cuevas, B.; Gonzalez-Corrochano, R.; Diaz-Gonzalez, D.; Reimers, D. Peripheral nerve regeneration by bone marrow stromal cells. Neurol. Res. 2002, 24, 634–638. [Google Scholar] [CrossRef] [PubMed]
  25. Nijhuis, T.H.; Bodar, C.W.; van Neck, J.W.; Walbeehm, E.T.; Siemionow, M.; Madajka, M.; Cwykiel, J.; Blok, J.H.; Hovius, S.E. Natural conduits for bridging a 15-mm nerve defect: Comparison of the vein supported by muscle and bone marrow stromal cells with a nerve autograft. J. Plast. Reconstr. Aesthet. Surg. JPRAS 2013, 66, 251–259. [Google Scholar] [CrossRef] [PubMed]
  26. Wang, Y.; Li, Z.W.; Luo, M.; Li, Y.J.; Zhang, K.Q. Biological conduits combining bone marrow mesenchymal stem cells and extracellular matrix to treat long-segment sciatic nerve defects. Neural Regen. Res. 2015, 10, 965–971. [Google Scholar] [PubMed]
  27. Carrier-Ruiz, A.; Evaristo-Mendonca, F.; Mendez-Otero, R.; Ribeiro-Resende, V.T. Biological behavior of mesenchymal stem cells on poly-epsilon-caprolactone filaments and a strategy for tissue engineering of segments of the peripheral nerves. Stem Cell Res. Ther. 2015, 6, 128. [Google Scholar] [CrossRef] [PubMed]
  28. Raheja, A.; Suri, V.; Suri, A.; Sarkar, C.; Srivastava, A.; Mohanty, S.; Jain, K.G.; Sharma, M.C.; Mallick, H.N.; Yadav, P.K.; et al. Dose-dependent facilitation of peripheral nerve regeneration by bone marrow-derived mononuclear cells: A randomized controlled study: Laboratory investigation. J. Neurosurg. 2012, 117, 1170–1181. [Google Scholar] [CrossRef] [PubMed]
  29. Hu, X.; Huang, X.; Yang, Q.; Wang, L.; Sun, J.; Zhan, H.; Lin, J.; Pu, Z.; Jiang, J.; Sun, Y.; et al. Safety and efficacy of intracoronary hypoxia-preconditioned bone marrow mononuclear cell administration for acute myocardial infarction patients: The China-AMI randomized controlled trial. Int. J. Cardiol. 2015, 184, 446–451. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. Rodrigo, S.F.; van Ramshorst, J.; Mann, I.; Leong, D.P.; Cannegieter, S.C.; Al Younis, I.; Dibbets-Schneider, P.; de Roos, A.; Fibbe, W.E.; Zwaginga, J.J.; et al. Predictors of response to intramyocardial bone marrow cell treatment in patients with refractory angina and chronic myocardial ischemia. Int. J. Cardiol. 2014, 175, 539–544. [Google Scholar] [CrossRef] [PubMed]
  31. Kumar, A.A.; Kumar, S.R.; Narayanan, R.; Arul, K.; Baskaran, M. Autologous bone marrow derived mononuclear cell therapy for spinal cord injury: A phase I/II clinical safety and primary efficacy data. Exp. Clin. Transplant. 2009, 7, 241–248. [Google Scholar] [PubMed]
  32. Gimble, J.M.; Bunnell, B.A.; Frazier, T.; Rowan, B.; Shah, F.; Thomas-Porch, C.; Wu, X. Adipose-derived stromal/stem cells: A primer. Organogenesis 2013, 9, 3–10. [Google Scholar] [CrossRef] [PubMed]
  33. Strem, B.M.; Hicok, K.C.; Zhu, M.; Wulur, I.; Alfonso, Z.; Schreiber, R.E.; Fraser, J.K.; Hedrick, M.H. Multipotential differentiation of adipose tissue-derived stem cells. Keio J. Med. 2005, 54, 132–141. [Google Scholar] [CrossRef] [PubMed]
  34. Kingham, P.J.; Kalbermatten, D.F.; Mahay, D.; Armstrong, S.J.; Wiberg, M.; Terenghi, G. Adipose-derived stem cells differentiate into a Schwann cell phenotype and promote neurite outgrowth in vitro. Exp. Neurol. 2007, 207, 267–274. [Google Scholar] [CrossRef] [PubMed]
  35. Ning, H.; Lin, G.; Lue, T.F.; Lin, C.S. Neuron-like differentiation of adipose tissue-derived stromal cells and vascular smooth muscle cells. Differentiation 2006, 74, 510–518. [Google Scholar] [CrossRef] [PubMed]
  36. Mantovani, C.; Raimondo, S.; Haneef, M.S.; Geuna, S.; Terenghi, G.; Shawcross, S.G.; Wiberg, M. Morphological, molecular and functional differences of adult bone marrow- and adipose-derived stem cells isolated from rats of different ages. Exp. Cell Res. 2012, 318, 2034–2048. [Google Scholar] [CrossRef] [PubMed]
  37. Tse, K.H.; Novikov, L.N.; Wiberg, M.; Kingham, P.J. Intrinsic mechanisms underlying the neurotrophic activity of adipose derived stem cells. Exp. Cell Res. 2015, 331, 142–151. [Google Scholar] [CrossRef] [PubMed]
  38. Kingham, P.J.; Kolar, M.K.; Novikova, L.N.; Novikov, L.N.; Wiberg, M. Stimulating the neurotrophic and angiogenic properties of human adipose-derived stem cells enhances nerve repair. Stem Cells Dev. 2014, 23, 741–754. [Google Scholar] [CrossRef] [PubMed]
  39. Sowa, Y.; Kishida, T.; Imura, T.; Numajiri, T.; Nishino, K.; Tabata, Y.; Mazda, O. Adipose-derived stem cells promote peripheral nerve regeneration in vivo without differentiation into schwann-like lineage. Plast. Reconstr. Surg. 2016, 137, 318e–330e. [Google Scholar] [CrossRef] [PubMed]
  40. Suganuma, S.; Tada, K.; Hayashi, K.; Takeuchi, A.; Sugimoto, N.; Ikeda, K.; Tsuchiya, H. Uncultured adipose-derived regenerative cells promote peripheral nerve regeneration. J. Orthop. Sci. 2013, 18, 145–151. [Google Scholar] [CrossRef] [PubMed]
  41. Klein, S.M.; Vykoukal, J.; Li, D.P.; Pan, H.L.; Zeitler, K.; Alt, E.; Geis, S.; Felthaus, O.; Prantl, L. Peripheral motor and sensory nerve conduction following transplantation of undifferentiated autologous adipose tissue-derived stem cells in a biodegradable US Food and drug administration-approved nerve conduit. Plast. Reconstr. Surg. 2016, 138, 132–139. [Google Scholar] [CrossRef] [PubMed]
  42. Carlson, K.B.; Singh, P.; Feaster, M.M.; Ramnarain, A.; Pavlides, C.; Chen, Z.L.; Yu, W.M.; Feltri, M.L.; Strickland, S. Mesenchymal stem cells facilitate axon sorting, myelination, and functional recovery in paralyzed mice deficient in schwann cell-derived laminin. Glia 2011, 59, 267–277. [Google Scholar] [CrossRef] [PubMed]
  43. Marconi, S.; Castiglione, G.; Turano, E.; Bissolotti, G.; Angiari, S.; Farinazzo, A.; Constantin, G.; Bedogni, G.; Bedogni, A.; Bonetti, B. Human adipose-derived mesenchymal stem cells systemically injected promote peripheral nerve regeneration in the mouse model of sciatic crush. Tissue Eng. Part A 2012, 18, 1264–1272. [Google Scholar] [CrossRef] [PubMed]
  44. Lasso, J.M.; Perez Cano, R.; Castro, Y.; Arenas, L.; Garcia, J.; Fernandez-Santos, M.E. Xenotransplantation of human adipose-derived stem cells in the regeneration of a rabbit peripheral nerve. J. Plast. Reconstr. Aesthet. Surg. JPRAS 2015, 68, e189–e197. [Google Scholar] [CrossRef] [PubMed]
  45. Zhao, L.; Wei, X.; Ma, Z.; Feng, D.; Tu, P.; Johnstone, B.H.; March, K.L.; Du, Y. Adipose stromal cells-conditional medium protected glutamate-induced cgns neuronal death by bdnf. Neurosci. Lett. 2009, 452, 238–240. [Google Scholar] [CrossRef] [PubMed]
  46. Sowa, Y.; Imura, T.; Numajiri, T.; Nishino, K.; Fushiki, S. Adipose-derived stem cells produce factors enhancing peripheral nerve regeneration: Influence of age and anatomic site of origin. Stem Cells Dev. 2012, 21, 1852–1862. [Google Scholar] [CrossRef] [PubMed]
  47. Erba, P.; Mantovani, C.; Kalbermatten, D.F.; Pierer, G.; Terenghi, G.; Kingham, P.J. Regeneration potential and survival of transplanted undifferentiated adipose tissue-derived stem cells in peripheral nerve conduits. J. Plast. Reconstr. Aesthet. Surg. JPRAS 2010, 63, e811–e817. [Google Scholar] [CrossRef] [PubMed]
  48. Nie, C.; Yang, D.; Xu, J.; Si, Z.; Jin, X.; Zhang, J. Locally administered adipose-derived stem cells accelerate wound healing through differentiation and vasculogenesis. Cell Transplant. 2011, 20, 205–216. [Google Scholar] [CrossRef] [PubMed]
  49. Chen, Y.T.; Sun, C.K.; Lin, Y.C.; Chang, L.T.; Chen, Y.L.; Tsai, T.H.; Chung, S.Y.; Chua, S.; Kao, Y.H.; Yen, C.H.; et al. Adipose-derived mesenchymal stem cell protects kidneys against ischemia-reperfusion injury through suppressing oxidative stress and inflammatory reaction. J. Transl. Med. 2011, 9, 51. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  50. Engels, P.E.; Tremp, M.; Kingham, P.J.; di Summa, P.G.; Largo, R.D.; Schaefer, D.J.; Kalbermatten, D.F. Harvest site influences the growth properties of adipose derived stem cells. Cytotechnology 2013, 65, 437–445. [Google Scholar] [CrossRef] [PubMed]
  51. Tremp, M.; Meyer Zu Schwabedissen, M.; Kappos, E.A.; Engels, P.E.; Fischmann, A.; Scherberich, A.; Schaefer, D.J.; Kalbermatten, D.F. The regeneration potential after human and autologous stem cell transplantation in a rat sciatic nerve injury model can be monitored by MRI. Cell Transplant. 2015, 24, 203–211. [Google Scholar] [PubMed]
  52. Faroni, A.; Smith, R.J.; Lu, L.; Reid, A.J. Human schwann-like cells derived from adipose-derived mesenchymal stem cells rapidly de-differentiate in the absence of stimulating medium. Eur. J. Neurosci. 2016, 43, 417–430. [Google Scholar] [CrossRef] [PubMed]
  53. Fairbairn, N.G.; Randolph, M.A.; Redmond, R.W. The clinical applications of human amnion in plastic surgery. J. Plast. Reconstr. Aesthet. Surg. JPRAS 2014, 67, 662–675. [Google Scholar] [CrossRef] [PubMed]
  54. Fu, Y.S.; Cheng, Y.C.; Lin, M.Y.; Cheng, H.; Chu, P.M.; Chou, S.C.; Shih, Y.H.; Ko, M.H.; Sung, M.S. Conversion of human umbilical cord mesenchymal stem cells in wharton’s jelly to dopaminergic neurons in vitro: Potential therapeutic application for parkinsonism. Stem Cells 2006, 24, 115–124. [Google Scholar] [CrossRef] [PubMed]
  55. Tsai, M.S.; Hwang, S.M.; Tsai, Y.L.; Cheng, F.C.; Lee, J.L.; Chang, Y.J. Clonal amniotic fluid-derived stem cells express characteristics of both mesenchymal and neural stem cells. Biol. Reprod. 2006, 74, 545–551. [Google Scholar] [CrossRef] [PubMed]
  56. Tsai, M.S.; Lee, J.L.; Chang, Y.J.; Hwang, S.M. Isolation of human multipotent mesenchymal stem cells from second-trimester amniotic fluid using a novel two-stage culture protocol. Hum. Reprod. 2004, 19, 1450–1456. [Google Scholar] [CrossRef] [PubMed]
  57. Li, Y.; Guo, L.; Ahn, H.S.; Kim, M.H.; Kim, S.W. Amniotic mesenchymal stem cells display neurovascular tropism and aid in the recovery of injured peripheral nerves. J. Cell. Mol. Med. 2014, 18, 1028–1034. [Google Scholar] [CrossRef] [PubMed]
  58. Pan, H.C.; Cheng, F.C.; Chen, C.J.; Lai, S.Z.; Lee, C.W.; Yang, D.Y.; Chang, M.H.; Ho, S.P. Post-injury regeneration in rat sciatic nerve facilitated by neurotrophic factors secreted by amniotic fluid mesenchymal stem cells. J. Clin. Neurosci. 2007, 14, 1089–1098. [Google Scholar] [CrossRef] [PubMed]
  59. Pan, H.C.; Yang, D.Y.; Ho, S.P.; Sheu, M.L.; Chen, C.J.; Hwang, S.M.; Chang, M.H.; Cheng, F.C. Escalated regeneration in sciatic nerve crush injury by the combined therapy of human amniotic fluid mesenchymal stem cells and fermented soybean extracts, natto. J. Biomed. Sci. 2009, 16, 75. [Google Scholar] [CrossRef] [PubMed]
  60. Cheng, F.C.; Tai, M.H.; Sheu, M.L.; Chen, C.J.; Yang, D.Y.; Su, H.L.; Ho, S.P.; Lai, S.Z.; Pan, H.C. Enhancement of regeneration with glia cell line-derived neurotrophic factor-transduced human amniotic fluid mesenchymal stem cells after sciatic nerve crush injury. J. Neurosurg. 2010, 112, 868–879. [Google Scholar] [CrossRef] [PubMed]
  61. Yang, D.Y.; Sheu, M.L.; Su, H.L.; Cheng, F.C.; Chen, Y.J.; Chen, C.J.; Chiu, W.T.; Yiin, J.J.; Sheehan, J.; Pan, H.C. Dual regeneration of muscle and nerve by intravenous administration of human amniotic fluid-derived mesenchymal stem cells regulated by stromal cell-derived factor-1alpha in a sciatic nerve injury model. J. Neurosurg. 2012, 116, 1357–1367. [Google Scholar] [CrossRef] [PubMed]
  62. Bongso, A.; Fong, C.Y.; Gauthaman, K. Taking stem cells to the clinic: Major challenges. J. Cell. Biochem. 2008, 105, 1352–1360. [Google Scholar] [CrossRef] [PubMed]
  63. Matsuse, D.; Kitada, M.; Kohama, M.; Nishikawa, K.; Makinoshima, H.; Wakao, S.; Fujiyoshi, Y.; Heike, T.; Nakahata, T.; Akutsu, H.; et al. Human umbilical cord-derived mesenchymal stromal cells differentiate into functional schwann cells that sustain peripheral nerve regeneration. J. Neuropathol. Exp. Neurol. 2010, 69, 973–985. [Google Scholar] [CrossRef] [PubMed]
  64. Guo, Z.Y.; Sun, X.; Xu, X.L.; Zhao, Q.; Peng, J.; Wang, Y. Human umbilical cord mesenchymal stem cells promote peripheral nerve repair via paracrine mechanisms. Neural Regen. Res. 2015, 10, 651–658. [Google Scholar] [PubMed]
  65. Zarbakhsh, S.; Goudarzi, N.; Shirmohammadi, M.; Safari, M. Histological study of bone marrow and umbilical cord stromal cell transplantation in regenerating rat peripheral nerve. Cell J. 2016, 17, 668–677. [Google Scholar] [PubMed]
  66. Raio, L.; Ghezzi, F.; Di Naro, E.; Gomez, R.; Franchi, M.; Mazor, M.; Bruhwiler, H. Sonographic measurement of the umbilical cord and fetal anthropometric parameters. Eur. J. Obstet. Gynecol. Reprod. Biol. 1999, 83, 131–135. [Google Scholar] [CrossRef]
  67. Wang, D.; Liu, X.L.; Zhu, J.K.; Jiang, L.; Hu, J.; Zhang, Y.; Yang, L.M.; Wang, H.G.; Yi, J.H. Bridging small-gap peripheral nerve defects using acellular nerve allograft implanted with autologous bone marrow stromal cells in primates. Brain Res. 2008, 1188, 44–53. [Google Scholar] [CrossRef] [PubMed]
  68. Peng, J.; Wang, Y.; Zhang, L.; Zhao, B.; Zhao, Z.; Chen, J.; Guo, Q.; Liu, S.; Sui, X.; Xu, W.; et al. Human umbilical cord wharton’s jelly-derived mesenchymal stem cells differentiate into a Schwann-cell phenotype and promote neurite outgrowth in vitro. Brain Res. Bull. 2011, 84, 235–243. [Google Scholar] [CrossRef] [PubMed]
  69. Biernaskie, J.A.; McKenzie, I.A.; Toma, J.G.; Miller, F.D. Isolation of skin-derived precursors (SKPs) and differentiation and enrichment of their Schwann cell progeny. Nat. Protoc. 2006, 1, 2803–2812. [Google Scholar] [CrossRef] [PubMed]
  70. McKenzie, I.A.; Biernaskie, J.; Toma, J.G.; Midha, R.; Miller, F.D. Skin-derived precursors generate myelinating schwann cells for the injured and dysmyelinated nervous system. J. Neurosci. 2006, 26, 6651–6660. [Google Scholar] [CrossRef] [PubMed]
  71. Khuong, H.T.; Kumar, R.; Senjaya, F.; Grochmal, J.; Ivanovic, A.; Shakhbazau, A.; Forden, J.; Webb, A.; Biernaskie, J.; Midha, R. Skin derived precursor schwann cells improve behavioral recovery for acute and delayed nerve repair. Exp. Neurol. 2014, 254, 168–179. [Google Scholar] [CrossRef] [PubMed]
  72. Grimoldi, N.; Colleoni, F.; Tiberio, F.; Vetrano, I.G.; Cappellari, A.; Costa, A.; Belicchi, M.; Razini, P.; Giordano, R.; Spagnoli, D.; et al. Stem cell salvage of injured peripheral nerve. Cell Transplant. 2015, 24, 213–222. [Google Scholar] [PubMed]
  73. Joannides, A.; Gaughwin, P.; Schwiening, C.; Majed, H.; Sterling, J.; Compston, A.; Chandran, S. Efficient generation of neural precursors from adult human skin: Astrocytes promote neurogenesis from skin-derived stem cells. Lancet 2004, 364, 172–178. [Google Scholar] [CrossRef]
  74. Yu, H.; Kumar, S.M.; Kossenkov, A.V.; Showe, L.; Xu, X. Stem cells with neural crest characteristics derived from the bulge region of cultured human hair follicles. J. Investig. Dermatol. 2010, 130, 1227–1236. [Google Scholar] [CrossRef] [PubMed]
  75. Amoh, Y.; Aki, R.; Hamada, Y.; Niiyama, S.; Eshima, K.; Kawahara, K.; Sato, Y.; Tani, Y.; Hoffman, R.M.; Katsuoka, K. Nestin-positive hair follicle pluripotent stem cells can promote regeneration of impinged peripheral nerve injury. J. Dermatol. 2012, 39, 33–38. [Google Scholar] [CrossRef] [PubMed]
  76. Lin, H.; Liu, F.; Zhang, C.; Zhang, Z.; Guo, J.; Ren, C.; Kong, Z. Pluripotent hair follicle neural crest stem-cell-derived neurons and schwann cells functionally repair sciatic nerves in rats. Mol. Neurobiol. 2009, 40, 216–223. [Google Scholar] [CrossRef] [PubMed]
  77. Gronthos, S.; Mankani, M.; Brahim, J.; Robey, P.G.; Shi, S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc. Natl. Acad. Sci. USA 2000, 97, 13625–13630. [Google Scholar] [CrossRef] [PubMed]
  78. Askari, N.; Yaghoobi, M.M.; Shamsara, M.; Esmaeili-Mahani, S. Tetracycline-regulated expression of OLIG2 gene in human dental pulp stem cells lead to mouse sciatic nerve regeneration upon transplantation. Neuroscience 2015, 305, 197–208. [Google Scholar] [CrossRef] [PubMed]
  79. Arthur, A.; Shi, S.; Zannettino, A.C.; Fujii, N.; Gronthos, S.; Koblar, S.A. Implanted adult human dental pulp stem cells induce endogenous axon guidance. Stem Cells 2009, 27, 2229–2237. [Google Scholar] [CrossRef] [PubMed]
  80. Martens, W.; Sanen, K.; Georgiou, M.; Struys, T.; Bronckaers, A.; Ameloot, M.; Phillips, J.; Lambrichts, I. Human dental pulp stem cells can differentiate into Schwann cells and promote and guide neurite outgrowth in an aligned tissue-engineered collagen construct in vitro. FASEB J. 2014, 28, 1634–1643. [Google Scholar] [CrossRef] [PubMed]
  81. Yamamoto, T.; Osako, Y.; Ito, M.; Murakami, M.; Hayashi, Y.; Horibe, H.; Iohara, K.; Takeuchi, N.; Okui, N.; Hirata, H.; et al. Trophic effects of dental pulp stem cells on Schwann cells in peripheral nerve regeneration. Cell Transplant. 2016, 25, 183–193. [Google Scholar] [CrossRef] [PubMed]
  82. Sugimura-Wakayama, Y.; Katagiri, W.; Osugi, M.; Kawai, T.; Ogata, K.; Sakaguchi, K.; Hibi, H. Peripheral nerve regeneration by secretomes of stem cells from human exfoliated deciduous teeth. Stem Cells Dev. 2015, 24, 2687–2699. [Google Scholar] [CrossRef] [PubMed]
  83. Alge, D.L.; Zhou, D.; Adams, L.L.; Wyss, B.K.; Shadday, M.D.; Woods, E.J.; Gabriel Chu, T.M.; Goebel, W.S. Donor-matched comparison of dental pulp stem cells and bone marrow-derived mesenchymal stem cells in a rat model. J. Tissue Eng. Regen. Med. 2010, 4, 73–81. [Google Scholar] [CrossRef] [PubMed]
  84. Hei, W.H.; Kim, S.; Park, J.C.; Seo, Y.K.; Kim, S.M.; Jahng, J.W.; Lee, J.H. Schwann-like cells differentiated from human dental pulp stem cells combined with a pulsed electromagnetic field can improve peripheral nerve regeneration. Bioelectromagnetics 2016, 37, 163–174. [Google Scholar] [CrossRef] [PubMed]
  85. Deasy, B.M.; Gharaibeh, B.M.; Pollett, J.B.; Jones, M.M.; Lucas, M.A.; Kanda, Y.; Huard, J. Long-term self-renewal of postnatal muscle-derived stem cells. Mol. Biol. Cell 2005, 16, 3323–3333. [Google Scholar] [CrossRef] [PubMed]
  86. Qu-Petersen, Z.; Deasy, B.; Jankowski, R.; Ikezawa, M.; Cummins, J.; Pruchnic, R.; Mytinger, J.; Cao, B.; Gates, C.; Wernig, A.; et al. Identification of a novel population of muscle stem cells in mice: Potential for muscle regeneration. J. Cell Biol. 2002, 157, 851–864. [Google Scholar] [CrossRef] [PubMed]
  87. Lavasani, M.; Thompson, S.D.; Pollett, J.B.; Usas, A.; Lu, A.; Stolz, D.B.; Clark, K.A.; Sun, B.; Peault, B.; Huard, J. Human muscle-derived stem/progenitor cells promote functional murine peripheral nerve regeneration. J. Clin. Investig. 2014, 124, 1745–1756. [Google Scholar] [CrossRef] [PubMed]
  88. Tamaki, T.; Soeda, S.; Hashimoto, H.; Saito, K.; Sakai, A.; Nakajima, N.; Masuda, M.; Fukunishi, N.; Uchiyama, Y.; Terachi, T.; et al. 3d reconstitution of nerve-blood vessel networks using skeletal muscle-derived multipotent stem cell sheet pellets. Regen. Med. 2013, 8, 437–451. [Google Scholar] [CrossRef] [PubMed]
  89. Bulken-Hoover, J.D.; Jackson, W.M.; Ji, Y.; Volger, J.A.; Tuan, R.S.; Nesti, L.J. Inducible expression of neurotrophic factors by mesenchymal progenitor cells derived from traumatically injured human muscle. Mol. Biotechnol. 2012, 51, 128–136. [Google Scholar] [CrossRef] [PubMed]
  90. Robinton, D.A.; Daley, G.Q. The promise of induced pluripotent stem cells in research and therapy. Nature 2012, 481, 295–305. [Google Scholar] [CrossRef] [PubMed]
  91. Denham, M.; Dottori, M. Neural differentiation of induced pluripotent stem cells. Methods Mol. Biol. 2011, 793, 99–110. [Google Scholar] [PubMed]
  92. Hu, B.Y.; Weick, J.P.; Yu, J.; Ma, L.X.; Zhang, X.Q.; Thomson, J.A.; Zhang, S.C. Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc. Natl. Acad. Sci. USA 2010, 107, 4335–4340. [Google Scholar] [CrossRef] [PubMed]
  93. Ikeda, M.; Uemura, T.; Takamatsu, K.; Okada, M.; Kazuki, K.; Tabata, Y.; Ikada, Y.; Nakamura, H. Acceleration of peripheral nerve regeneration using nerve conduits in combination with induced pluripotent stem cell technology and a basic fibroblast growth factor drug delivery system. J. Biomed. Mater. Res. Part A 2014, 102, 1370–1378. [Google Scholar] [CrossRef] [PubMed]
  94. Uemura, T.; Takamatsu, K.; Ikeda, M.; Okada, M.; Kazuki, K.; Ikada, Y.; Nakamura, H. A tissue-engineered bioabsorbable nerve conduit created by three-dimensional culture of induced pluripotent stem cell-derived neurospheres. Bio-Med. Mater. Eng. 2011, 21, 333–339. [Google Scholar]
  95. Uemura, T.; Ikeda, M.; Takamatsu, K.; Yokoi, T.; Okada, M.; Nakamura, H. Long-term efficacy and safety outcomes of transplantation of induced pluripotent stem cell-derived neurospheres with bioabsorbable nerve conduits for peripheral nerve regeneration in mice. Cells Tissues Organs 2014, 200, 78–91. [Google Scholar] [CrossRef] [PubMed]
  96. Ben-David, U.; Benvenisty, N. The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat. Rev. Cancer 2011, 11, 268–277. [Google Scholar] [CrossRef] [PubMed]
  97. Sanchez-Ramos, J.; Song, S.; Cardozo-Pelaez, F.; Hazzi, C.; Stedeford, T.; Willing, A.; Freeman, T.B.; Saporta, S.; Janssen, W.; Patel, N.; et al. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp. Neurol. 2000, 164, 247–256. [Google Scholar] [CrossRef] [PubMed]
  98. Dore, J.J.; DeWitt, J.C.; Setty, N.; Donald, M.D.; Joo, E.; Chesarone, M.A.; Birren, S.J. Multiple signaling pathways converge to regulate bone-morphogenetic-protein-dependent glial gene expression. Dev. Neurosci. 2009, 31, 473–486. [Google Scholar] [CrossRef] [PubMed]
  99. Dezawa, M.; Kanno, H.; Hoshino, M.; Cho, H.; Matsumoto, N.; Itokazu, Y.; Tajima, N.; Yamada, H.; Sawada, H.; Ishikawa, H.; et al. Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J. Clin. Investig. 2004, 113, 1701–1710. [Google Scholar] [CrossRef] [PubMed]
  100. Chen, Y.; Teng, F.Y.; Tang, B.L. Coaxing bone marrow stromal mesenchymal stem cells towards neuronal differentiation: Progress and uncertainties. Cell. Mol. Life Sci. 2006, 63, 1649–1657. [Google Scholar] [CrossRef] [PubMed]
  101. Ma, M.S.; Boddeke, E.; Copray, S. Pluripotent stem cells for schwann cell engineering. Stem Cell Rev. 2015, 11, 205–218. [Google Scholar] [CrossRef] [PubMed]
  102. Orbay, H.; Uysal, A.C.; Hyakusoku, H.; Mizuno, H. Differentiated and undifferentiated adipose-derived stem cells improve function in rats with peripheral nerve gaps. J. Plast. Reconstr. Aesthet. Surg. 2012, 65, 657–664. [Google Scholar] [CrossRef] [PubMed]
  103. Shea, G.K.; Tsui, A.Y.; Chan, Y.S.; Shum, D.K. Bone marrow-derived schwann cells achieve fate commitment—A prerequisite for remyelination therapy. Exp. Neurol. 2010, 224, 448–458. [Google Scholar] [CrossRef] [PubMed]
  104. Wang, X.; Luo, E.; Li, Y.; Hu, J. Schwann-like mesenchymal stem cells within vein graft facilitate facial nerve regeneration and remyelination. Brain Res. 2011, 1383, 71–80. [Google Scholar] [CrossRef] [PubMed]
  105. Tomita, K.; Madura, T.; Mantovani, C.; Terenghi, G. Differentiated adipose-derived stem cells promote myelination and enhance functional recovery in a rat model of chronic denervation. J. Neurosci. Res. 2012, 90, 1392–1402. [Google Scholar] [CrossRef] [PubMed]
  106. Di Summa, P.G.; Kingham, P.J.; Campisi, C.C.; Raffoul, W.; Kalbermatten, D.F. Collagen (NeuraGen®) nerve conduits and stem cells for peripheral nerve gap repair. Neurosci. Lett. 2014, 572, 26–31. [Google Scholar] [CrossRef] [PubMed]
  107. Swijnenburg, R.J.; Schrepfer, S.; Cao, F.; Pearl, J.I.; Xie, X.; Connolly, A.J.; Robbins, R.C.; Wu, J.C. In vivo imaging of embryonic stem cells reveals patterns of survival and immune rejection following transplantation. Stem Cells Dev. 2008, 17, 1023–1029. [Google Scholar] [CrossRef] [PubMed]
  108. Walsh, S.; Midha, R. Practical considerations concerning the use of stem cells for peripheral nerve repair. Neurosurg. Focus 2009, 26, E2. [Google Scholar] [CrossRef] [PubMed]
  109. Chen, Q.; Long, Y.; Yuan, X.; Zou, L.; Sun, J.; Chen, S.; Perez-Polo, J.R.; Yang, K. Protective effects of bone marrow stromal cell transplantation in injured rodent brain: Synthesis of neurotrophic factors. J. Neurosci. Res. 2005, 80, 611–619. [Google Scholar] [CrossRef] [PubMed]
  110. Reid, A.J.; Sun, M.; Wiberg, M.; Downes, S.; Terenghi, G.; Kingham, P.J. Nerve repair with adipose-derived stem cells protects dorsal root ganglia neurons from apoptosis. Neuroscience 2011, 199, 515–522. [Google Scholar] [CrossRef] [PubMed]
  111. Ribeiro-Resende, V.T.; Pimentel-Coelho, P.M.; Mesentier-Louro, L.A.; Mendez, R.M.; Mello-Silva, J.P.; Cabral-da-Silva, M.C.; de Mello, F.G.; de Melo Reis, R.A.; Mendez-Otero, R. Trophic activity derived from bone marrow mononuclear cells increases peripheral nerve regeneration by acting on both neuronal and glial cell populations. Neuroscience 2009, 159, 540–549. [Google Scholar] [CrossRef] [PubMed]
  112. Lopatina, T.; Kalinina, N.; Karagyaur, M.; Stambolsky, D.; Rubina, K.; Revischin, A.; Pavlova, G.; Parfyonova, Y.; Tkachuk, V. Adipose-derived stem cells stimulate regeneration of peripheral nerves: Bdnf secreted by these cells promotes nerve healing and axon growth de novo. PLoS ONE 2011, 6, e17899. [Google Scholar] [CrossRef] [PubMed]
  113. Xu, Y.; Liu, L.; Li, Y.; Zhou, C.; Xiong, F.; Liu, Z.; Gu, R.; Hou, X.; Zhang, C. Myelin-forming ability of schwann cell-like cells induced from rat adipose-derived stem cells in vitro. Brain Res. 2008, 1239, 49–55. [Google Scholar] [CrossRef] [PubMed]
  114. Garbay, B.; Heape, A.M.; Sargueil, F.; Cassagne, C. Myelin synthesis in the peripheral nervous system. Prog. Neurobiol. 2000, 61, 267–304. [Google Scholar] [CrossRef]
  115. Zhang, Q.; Nguyen, P.; Xu, Q.; Park, W.; Lee, S.; Furuhashi, A.; Le, A.D. Neural progenitor-like cells induced from human gingiva-derived mesenchymal stem cells regulate myelination of schwann cells in rat sciatic nerve regeneration. Stem Cells Transl. Med. 2016, 5, 1–13. [Google Scholar] [CrossRef] [PubMed]
  116. Pang, C.J.; Tong, L.; Ji, L.L.; Wang, Z.Y.; Zhang, X.; Gao, H.; Jia, H.; Zhang, L.X.; Tong, X.J. Synergistic effects of ultrashort wave and bone marrow stromal cells on nerve regeneration with acellular nerve allografts. Synapse 2013, 67, 637–647. [Google Scholar] [CrossRef] [PubMed]
  117. Zhao, Z.; Wang, Y.; Peng, J.; Ren, Z.; Zhang, L.; Guo, Q.; Xu, W.; Lu, S. Improvement in nerve regeneration through a decellularized nerve graft by supplementation with bone marrow stromal cells in fibrin. Cell Transplant. 2014, 23, 97–110. [Google Scholar] [CrossRef] [PubMed]
  118. Tse, C.; Whiteley, R.; Yu, T.; Stringer, J.; MacNeil, S.; Haycock, J.W.; Smith, P.J. Inkjet printing Schwann cells and neuronal analogue NG108–15 cells. Biofabrication 2016, 8, 015017. [Google Scholar] [CrossRef] [PubMed]
  119. Johnson, B.N.; Jia, X. 3D printed nerve guidance channels: Computer-aided control of geometry, physical cues, biological supplements and gradients. Neural. Regen. Res. 2016, 11, 1568–1569. [Google Scholar] [CrossRef] [PubMed]
  120. Johnson, B.N.; Lancaster, K.Z.; Zhen, G.; He, J.; Gupta, M.K.; Kong, Y.L.; Engel, E.A.; Krick, K.D.; Ju, A.; Meng, F.; et al. 3d printed anatomical nerve regeneration pathways. Adv. Funct. Mater. 2015, 25, 6205–6217. [Google Scholar] [CrossRef] [PubMed]
  121. Weightman, A.; Jenkins, S.; Pickard, M.; Chari, D.; Yang, Y. Alignment of multiple glial cell populations in 3D nanofiber scaffolds: Toward the development of multicellular implantable scaffolds for repair of neural injury. Nanomedicine 2014, 10, 291–295. [Google Scholar] [CrossRef] [PubMed]
  122. Hu, Y.; Wu, Y.; Gou, Z.; Tao, J.; Zhang, J.; Liu, Q.; Kang, T.; Jiang, S.; Huang, S.; He, J.; et al. 3D-engineering of cellularized conduits for peripheral nerve regeneration. Sci. Rep. 2016, 6, 32184. [Google Scholar] [CrossRef] [PubMed]
  123. Costa, H.J.; Ferreira Bento, R.; Salomone, R.; Azzi-Nogueira, D.; Zanatta, D.B.; Paulino Costa, M.; da Silva, C.F.; Strauss, B.E.; Haddad, L.A. Mesenchymal bone marrow stem cells within polyglycolic acid tube observed in vivo after six weeks enhance facial nerve regeneration. Brain Res. 2013, 1510, 10–21. [Google Scholar] [CrossRef] [PubMed]
  124. Yang, Y.; Yuan, X.; Ding, F.; Yao, D.; Gu, Y.; Liu, J.; Gu, X. Repair of rat sciatic nerve gap by a silk fibroin-based scaffold added with bone marrow mesenchymal stem cells. Tissue Eng. Part A 2011, 17, 2231–2244. [Google Scholar] [CrossRef] [PubMed]
  125. Wakao, S.; Hayashi, T.; Kitada, M.; Kohama, M.; Matsue, D.; Teramoto, N.; Ose, T.; Itokazu, Y.; Koshino, K.; Watabe, H.; et al. Long-term observation of auto-cell transplantation in non-human primate reveals safety and efficiency of bone marrow stromal cell-derived Schwann cells in peripheral nerve regeneration. Exp. Neurol. 2010, 223, 537–547. [Google Scholar] [CrossRef] [PubMed]
  126. Pereira Lopes, F.R.; Camargo de Moura Campos, L.; Dias Correa J., Jr.; Balduino, A.; Lora, S.; Langone, F.; Borojevic, R.; Blanco Martinez, A.M. Bone marrow stromal cells and resorbable collagen guidance tubes enhance sciatic nerve regeneration in mice. Exp. Neurol. 2006, 198, 457–468. [Google Scholar] [CrossRef] [PubMed]
  127. Di Summa, P.G.; Kalbermatten, D.F.; Pralong, E.; Raffoul, W.; Kingham, P.J.; Terenghi, G. Long-term in vivo regeneration of peripheral nerves through bioengineered nerve grafts. Neuroscience 2011, 181, 278–291. [Google Scholar] [CrossRef] [PubMed]
  128. Hu, N.; Wu, H.; Xue, C.; Gong, Y.; Wu, J.; Xiao, Z.; Yang, Y.; Ding, F.; Gu, X. Long-term outcome of the repair of 50 mm long median nerve defects in rhesus monkeys with marrow mesenchymal stem cells-containing, chitosan-based tissue engineered nerve grafts. Biomaterials 2013, 34, 100–111. [Google Scholar] [CrossRef] [PubMed]
  129. Gu, Y.; Li, Z.; Huang, J.; Wang, H.; Gu, X.; Gu, J. Application of marrow mesenchymal stem cell-derived extracellular matrix in peripheral nerve tissue engineering. J. Tissue Eng. Regen. Med. 2016. [Google Scholar] [CrossRef] [PubMed]
  130. Tohill, M.; Mantovani, C.; Wiberg, M.; Terenghi, G. Rat bone marrow mesenchymal stem cells express glial markers and stimulate nerve regeneration. Neurosci. Lett. 2004, 362, 200–203. [Google Scholar] [CrossRef] [PubMed]
  131. Salomone, R.; Bento, R.F.; Costa, H.J.; Azzi-Nogueira, D.; Ovando, P.C.; Da-Silva, C.F.; Zanatta, D.B.; Strauss, B.E.; Haddad, L.A. Bone marrow stem cells in facial nerve regeneration from isolated stumps. Muscle Nerve 2013, 48, 423–429. [Google Scholar] [CrossRef] [PubMed]
  132. Kappos, E.A.; Engels, P.E.; Tremp, M.; Meyer zu Schwabedissen, M.; di Summa, P.; Fischmann, A.; von Felten, S.; Scherberich, A.; Schaefer, D.J.; Kalbermatten, D.F. Peripheral nerve repair: Multimodal comparison of the long-term regenerative potential of adipose tissue-derived cells in a biodegradable conduit. Stem Cells Dev. 2015, 24, 2127–2141. [Google Scholar] [CrossRef] [PubMed]
  133. Bell, J.H.; Haycock, J.W. Next generation nerve guides: Materials, fabrication, growth factors, and cell delivery. Tissue Eng. Part B Rev. 2012, 18, 116–128. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. Mechanism of stem cell transplantation for peripheral nerve injury (PNI) regeneration.
Figure 1. Mechanism of stem cell transplantation for peripheral nerve injury (PNI) regeneration.
Ijms 18 00094 g001
Table
Table 1. Comparison of stem cells from different sources in peripheral nerve regeneration. ESCs: embryonic stem cells; NSCs: neural stem cells; BMSCs: bone marrow-derived stem cells; ADSCs: adipose-derived stem cells; SKP-SCs: skin-derived precursor stem cells; HFSCs: hair follicle stem cells; DPSCs: dental pulp stem cells; MDSPCs: muscle-derived stem/progenitor cells; iPSCs: induced pluripotential stem cells; SCs: Schwann cells.
Table 1. Comparison of stem cells from different sources in peripheral nerve regeneration. ESCs: embryonic stem cells; NSCs: neural stem cells; BMSCs: bone marrow-derived stem cells; ADSCs: adipose-derived stem cells; SKP-SCs: skin-derived precursor stem cells; HFSCs: hair follicle stem cells; DPSCs: dental pulp stem cells; MDSPCs: muscle-derived stem/progenitor cells; iPSCs: induced pluripotential stem cells; SCs: Schwann cells.
Stem CellClassificationAdvantageDisadvantagePreclinical or Clinical UseMechanism
ESCsPluripotent stem cellsHomogenous, no detrimental impact of age and disease, unlimited cell number, better differentiation potential, and longer lasting proliferation capacityTeratoma formation, ethical dilemmaPreclinical [8,9]Myelination and/or neurotrophic factors
NSCsMultipotent stem cells Difficult to be harvestedPreclinical [15,16]Replace Schwann cells
BMSCsMultipotent cellsEasily accessible without ethical concernsLower capacity of proliferation and differentiation, invasive procedure for autologous harvestingPreclinical [25,26]Myelination, neurotrophic factors
ADSCsMultipotent stem cellsEasy to harvest, higher proportion and superior proliferationDifferentiation potential towards adipocytesPreclinical [40,41,42,43]Myelination, neurotrophic factors, reduce inflammation
Fetal-derived stem cellMultipotent stem cellsLess immunoreactivityCell bank for storagePreclinical [57,58,65,68]Augmented blood perfusion and enhanced intraneural vascularity
SKP-SCsMultipotent cellsEasy to harvestLong time to differentiatePreclinical [71]Replace Schwann cell myelination
HFSCsMultipotent stem cellsAbundant and accessible source, differentiate into pure human SC populationDifficult to isolatePreclinical [75]Replace Schwann cell myelination, neurotrophic factors
DPSCsMultipotent stem cellsStronger harvesting and proliferation potential, as well as greater clonogenic potentialRequire storagePreclinical [80,81]Replace Schwann cell myelination, neurotrophic factors
MDSPCsProgenitor cellsAbundant and accessible sourceLimited researchPreclinical [89]Neurotrophic factors
iPSCsPluripotent stem cellsInducible from easily obtainable somatic cellsSubdued efficiency and enhanced variability during the differentiation process, epigenetic memory from the original somatic cells, chromosomal aberrations, stronger tumorigenicityPreclinical [93]Replace Schwann cell myelination, neurotrophic factors
Table
Table 2. Stem cells delivery in peripheral nerve regeneration.
Table 2. Stem cells delivery in peripheral nerve regeneration.
MethodsApplicationAdvantage and DisadvantageReferences
Micro injection Traumatic both to the stem cells and delicate intra-neural architecture, abnormal cell distributionPang [116]
ConduitNatural conduits or artificialDifficult for cell deliveryNijhuis [25] Costa [123] Yang [124] Carrier-Ruiz [27] Wakao [125]
Conduit + ECMCollagen, fibirinGood cell distribution, lack of 3-D constructionPereira [126] di Summa [127]
Conduit + internal Beneficial for axonal guidanceWakao [125] Hu [128] Gu [129]
3-D print Customization, good cell distributionWeightman [121] Hu [122] Tse [118]

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Jiang, L.; Jones, S.; Jia, X. Stem Cell Transplantation for Peripheral Nerve Regeneration: Current Options and Opportunities. Int. J. Mol. Sci. 2017, 18, 94. https://doi.org/10.3390/ijms18010094

AMA Style

Jiang L, Jones S, Jia X. Stem Cell Transplantation for Peripheral Nerve Regeneration: Current Options and Opportunities. International Journal of Molecular Sciences. 2017; 18(1):94. https://doi.org/10.3390/ijms18010094

Chicago/Turabian Style

Jiang, Liangfu, Salazar Jones, and Xiaofeng Jia. 2017. "Stem Cell Transplantation for Peripheral Nerve Regeneration: Current Options and Opportunities" International Journal of Molecular Sciences 18, no. 1: 94. https://doi.org/10.3390/ijms18010094

APA Style

Jiang, L., Jones, S., & Jia, X. (2017). Stem Cell Transplantation for Peripheral Nerve Regeneration: Current Options and Opportunities. International Journal of Molecular Sciences, 18(1), 94. https://doi.org/10.3390/ijms18010094

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