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Bioengineering
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Mesenchymal Stem Cells in Regenerative Medicine
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Mesenchymal Stem Cells in Regenerative Medicine

A special issue of Bioengineering (ISSN 2306-5354). This special issue belongs to the section "Regenerative Engineering".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 23476

Special Issue Editors

Dr. Ján Lakota

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Guest Editor
Centre of Experimental Medicine, SAS, Dubravska cesta 9, 841 04 Bratislava, Slovakia
Interests: stem cells; regenerative medicine
Prof. Dr. Joaquim M. S. Cabral

E-Mail Website
Guest Editor
Department of Bioengineering and iBB- Institute of Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa , Portugal
Interests: stem cells research for tissue engineering and regenerative medicine; stem cell bioprocessing and manufacturing: development of novel stem cell bioreactors and advanced bioseparation and purification processes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

I would like to cordially invite you to submit a research/review paper to the Special Issue “Mesenchymal Stem Cells” (the open access journal Bioengineering (ISSN 2306-5354)).  The Mesenchymal Stem Cells (MSC) were discovered in the sixties of the 20th century. MSCs are situated in almost all organs and tissues of the human body. For practical purposes they are isolated and ex vivo expanded mainly from two main sources - from the bone marrow and fat tissue. Their expansion and isolation is rather simple and doesn’t require any sophisticated equipment. For decades they were used in regenerative medicine to treat previously “untreatable”. Nevertheless, we do need rules and data which are clear and without doubts. We need to follow “good biological practice” i.e. to work in the terms of real biology. The administrative rules should follow the biological laws and not vice versa. One needs to be careful not to blindly apply data obtained on rodents to humans. The gap between species is too bright. We need to solve other fundamental questions: Should the source of MSC be allogeneic or autologous? Are the autologous MSC “ill” with the patient? Can the huge amounts of ex vivo expanded MSC overcome their “illness”? How about the immune system of the host after administration of allogeneic MSC?  And finally – what is the mechanism of action of repair and regeneration after MSCs administration?

Dr. Ján Lakota
Prof. Dr. Joaquim M. S. Cabral
Guest Editors

Manuscript Submission Information

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Published Papers (8 papers)

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Research

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16 pages, 3863 KiB  
Article
The Osteogenic Potential of Falciform Ligament-Derived Stromal Cells—A Comparative Analysis between Two Osteogenic Induction Programs
by Carla Ferreira-Baptista, André Queirós, Rita Ferreira, Maria Helena Fernandes, Bruno Colaço and Pedro Sousa Gomes
Bioengineering 2022, 9(12), 810; https://doi.org/10.3390/bioengineering9120810 - 15 Dec 2022
Cited by 2 | Viewed by 1825
Abstract
Mesenchymal stromal cells (MSCs) have gained special relevance in bone tissue regenerative applications. MSCs have been isolated from different depots, with adipose tissue being acknowledged as one of the most convenient sources, given the wide availability, high cellular yield, and obtainability. Recently, the [...] Read more.
Mesenchymal stromal cells (MSCs) have gained special relevance in bone tissue regenerative applications. MSCs have been isolated from different depots, with adipose tissue being acknowledged as one of the most convenient sources, given the wide availability, high cellular yield, and obtainability. Recently, the falciform ligament (FL) has been regarded as a potential depot for adipose tissue-derived stromal cells (FL-ADSCs) isolation. Nonetheless, the osteogenic capability of FL-ADSCs has not been previously characterized. Thus, the present study aimed the detailed characterization of FL-ADSCs’ functionality upon osteogenic induction through a classic (dexamethasone-based-DEX) or an innovative strategy with retinoic acid (RA) in a comparative approach with ADSCs from a control visceral region. Cultures were characterized for cell proliferation, metabolic activity, cellular morphology, fluorescent cytoskeletal and mitochondrial organization, and osteogenic activity–gene expression analysis and cytochemical staining. FL-derived populations expressed significantly higher levels of osteogenic genes and cytochemical markers, particularly with DEX induction, as compared to control ADSCs that were more responsive to RA. FL-ADSCs were identified as a potential source for bone regenerative applications, given the heightened osteogenic functionality. Furthermore, data highlighted the importance of the selection of the most adequate osteogenic-inducing program concerning the specificities of the basal cell population. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells in Regenerative Medicine)
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23 pages, 7494 KiB  
Article
Hypothermic Preservation of Adipose-Derived Mesenchymal Stromal Cells as a Viable Solution for the Storage and Distribution of Cell Therapy Products
by André Branco, Ana L. Tiago, Paula Laranjeira, Maria C. Carreira, João C. Milhano, Francisco dos Santos, Joaquim M. S. Cabral, Artur Paiva, Cláudia L. da Silva and Ana Fernandes-Platzgummer
Bioengineering 2022, 9(12), 805; https://doi.org/10.3390/bioengineering9120805 - 14 Dec 2022
Cited by 4 | Viewed by 2939
Abstract
Cell and gene therapies (CGT) have reached new therapeutic targets but have noticeably high prices. Solutions to reduce production costs might be found in CGT storage and transportation since they typically involve cryopreservation, which is a heavily burdened process. Encapsulation at hypothermic temperatures [...] Read more.
Cell and gene therapies (CGT) have reached new therapeutic targets but have noticeably high prices. Solutions to reduce production costs might be found in CGT storage and transportation since they typically involve cryopreservation, which is a heavily burdened process. Encapsulation at hypothermic temperatures (e.g., 2–8 °C) could be a feasible alternative. Adipose tissue-derived mesenchymal stromal cells (MSC(AT)) expanded using fetal bovine serum (FBS)- (MSC-FBS) or human platelet lysate (HPL)-supplemented mediums (MSC-HPL) were encapsulated in alginate beads for 30 min, 5 days, and 12 days. After bead release, cell recovery and viability were determined to assess encapsulation performance. MSC identity was verified by flow cytometry, and a set of assays was performed to evaluate functionality. MSC(AT) were able to survive encapsulated for a standard transportation period of 5 days, with recovery values of 56 ± 5% for MSC-FBS and 77 ± 6% for MSC-HPL (which is a negligible drop compared to earlier timepoints). Importantly, MSC function did not suffer from encapsulation, with recovered cells showing robust differentiation potential, expression of immunomodulatory molecules, and hematopoietic support capacity. MSC(AT) encapsulation was proven possible for a remarkable 12 day period. There is currently no solution to completely replace cryopreservation in CGT logistics and supply chain, although encapsulation has shown potential to act as a serious competitor. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells in Regenerative Medicine)
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12 pages, 2113 KiB  
Article
Identification of the Factor That Leads Human Mesenchymal Stem Cell Lines into Decellularized Bone
by Anri Koyanagi, Iichiroh Onishi, Karin Muraoka, Ikue Sato, Shingo Sato, Tsuyoshi Kimura, Akio Kishida, Kouhei Yamamoto, Masanobu Kitagawa and Morito Kurata
Bioengineering 2022, 9(10), 490; https://doi.org/10.3390/bioengineering9100490 - 21 Sep 2022
Cited by 1 | Viewed by 2124
Abstract
Hematopoiesis is maintained by the interaction of hematopoietic stem cells (HSCs) and bone marrow mesenchymal stem cells (MSCs) in bone marrow microenvironments, called niches. Certain genetic mutations in MSCs, not HSCs, provoke some hematopoietic neoplasms, such as myelodysplastic syndrome. An in vivo bone [...] Read more.
Hematopoiesis is maintained by the interaction of hematopoietic stem cells (HSCs) and bone marrow mesenchymal stem cells (MSCs) in bone marrow microenvironments, called niches. Certain genetic mutations in MSCs, not HSCs, provoke some hematopoietic neoplasms, such as myelodysplastic syndrome. An in vivo bone marrow niche model using human MSC cell lines with specific genetic mutations and bone scaffolds is necessary to elucidate these interactions and the disease onset. We focused on decellularized bone (DCB) as a useful bone scaffold and attempted to induce human MSCs (UE7T-9 cells) into the DCB. Using the CRISPR activation library, we identified SHC4 upregulation as a candidate factor, with the SHC4 overexpression in UE7T-9 cells activating their migratory ability and upregulating genes to promote hematopoietic cell migration. This is the first study to apply the CRISPR library to engraft cells into decellularized biomaterials. SHC4 overexpression is essential for engrafting UE7T-9 cells into DCB, and it might be the first step toward creating an in vivo human–mouse hybrid bone marrow niche model. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells in Regenerative Medicine)
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22 pages, 11742 KiB  
Article
Mesenchymal Stem Cell Use in Acute Tendon Injury: In Vitro Tenogenic Potential vs. In Vivo Dose Response
by Kristin Bowers, Lisa Amelse, Austin Bow, Steven Newby, Amber MacDonald, Xiaocun Sun, David Anderson and Madhu Dhar
Bioengineering 2022, 9(8), 407; https://doi.org/10.3390/bioengineering9080407 - 22 Aug 2022
Cited by 4 | Viewed by 3162
Abstract
Stem cell therapy for the treatment of tendon injury is an emerging clinical practice in the fields of human and veterinary sports medicine; however, the therapeutic benefit of intralesional transplantation of mesenchymal stem cells in tendonitis cases is not well designed. Questions persist [...] Read more.
Stem cell therapy for the treatment of tendon injury is an emerging clinical practice in the fields of human and veterinary sports medicine; however, the therapeutic benefit of intralesional transplantation of mesenchymal stem cells in tendonitis cases is not well designed. Questions persist regarding the overall tenogenic potential and efficacy of this treatment alone. In this study, we aimed to isolate a rat mesenchymal stem cell lineage for in vitro and in vivo use, to assess the effects of growth factor exposure in vitro on cell morphology, behavior, and tendon-associated glycoprotein production, and to assess the therapeutic potential of intralesional stem cells, as a function of dose, in vivo. First, rat adipose-derived (rAdMSC) and bone marrow-derived (rBMSC) stem cell lineages were isolated, characterized with flow cytometric analysis, and compared in terms of proliferation (MTS assay) and cellular viability (calcein AM staining). Rat AdMSCs displayed superior proliferation and more homogenous CD 73, CD 44H, and CD 90 expression as compared to rBMSC. Next, the tenogenic differentiation potential of the rAdMSC lineage was tested in vitro through isolated and combined stimulation with reported tenogenic growth factors, transforming growth factor (TGF)-β3 and connective tissue growth factor (CTGF). We found that the most effective tenogenic factor in terms of cellular morphologic change, cell alignment/orientation, sustained cellular viability, and tendon-associated glycoprotein upregulation was TGFβ3, and we confirmed that rAdMSC could be induced toward a tenogenic lineage in vitro. Finally, the therapeutic potential of rAdMSCs as a function of dose was assessed using a rat acute Achilles tendon injury model. Amounts of 5 × 105 (low dose) and 4 × 106 (high dose) were used. Subjectively, on the gross morphology, the rAdMSC-treated tendons exhibited fewer adhesions and less scar tissue than the control tendons; however, regardless of the rAdMSC dose, no significant differences in histological grade or tissue collagen I deposition were noted between the rAdMSC-treated and control tendons. Collectively, rAdMSCs exhibited appropriate stem cell markers and tenogenic potential in vitro, but the clinical efficacy of intralesional implantation of undifferentiated cells in acute tendonitis cases could not be proven. Further investigation into complementary therapeutics or specialized culture conditions prior to implantation are warranted. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells in Regenerative Medicine)
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16 pages, 2559 KiB  
Article
HLA-A2 Promotes the Therapeutic Effect of Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Hyperoxic Lung Injury
by Jihye Kwak, Wankyu Choi, Yunkyung Bae, Miyeon Kim, Soojin Choi, Wonil Oh and Hyejin Jin
Bioengineering 2022, 9(4), 177; https://doi.org/10.3390/bioengineering9040177 - 18 Apr 2022
Viewed by 2903
Abstract
Mesenchymal stem cells (MSCs) are one of the most extensively studied stem cell types owing to their capacity for differentiation into multiple lineages as well as their ability to secrete regenerative factors and modulate immune functions. However, issues remain regarding their further application [...] Read more.
Mesenchymal stem cells (MSCs) are one of the most extensively studied stem cell types owing to their capacity for differentiation into multiple lineages as well as their ability to secrete regenerative factors and modulate immune functions. However, issues remain regarding their further application for cell therapy. Here, to demonstrate the superiority of the improvement of MSCs, we divided umbilical cord blood-derived MSCs (UCB-MSCs) from 15 donors into two groups based on efficacy and revealed donor-dependent variations in the anti-inflammatory effect of MSCs on macrophages as well as their immunoregulatory effect on T cells. Through surface marker analyses (242 antibodies), we found that HLA-A2 was positively related to the anti-inflammatory and immunoregulatory function of MSCs. Additionally, HLA-A2 mRNA silencing in MSCs attenuated their therapeutic effects in vitro; namely, the suppression of LPS-stimulated macrophages and phytohemagglutinin-stimulated T cells. Moreover, HLA-A2 silencing in MSCs significantly decreased their therapeutic effects in a rat model of hyperoxic lung damage. The present study provides novel insights into the quality control of donor-derived MSCs for the treatment of inflammatory conditions and diseases. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells in Regenerative Medicine)
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Review

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13 pages, 1457 KiB  
Review
Mesenchymal Stromal Cell Therapy in Lung Transplantation
by Antti I. Nykänen, Mingyao Liu and Shaf Keshavjee
Bioengineering 2023, 10(6), 728; https://doi.org/10.3390/bioengineering10060728 - 17 Jun 2023
Cited by 4 | Viewed by 3143
Abstract
Lung transplantation is often the only viable treatment option for a patient with end-stage lung disease. Lung transplant results have improved substantially over time, but ischemia-reperfusion injury, primary graft dysfunction, acute rejection, and chronic lung allograft dysfunction (CLAD) continue to be significant problems. [...] Read more.
Lung transplantation is often the only viable treatment option for a patient with end-stage lung disease. Lung transplant results have improved substantially over time, but ischemia-reperfusion injury, primary graft dysfunction, acute rejection, and chronic lung allograft dysfunction (CLAD) continue to be significant problems. Mesenchymal stromal cells (MSC) are pluripotent cells that have anti-inflammatory and protective paracrine effects and may be beneficial in solid organ transplantation. Here, we review the experimental studies where MSCs have been used to protect the donor lung against ischemia-reperfusion injury and alloimmune responses, as well as the experimental and clinical studies using MSCs to prevent or treat CLAD. In addition, we outline ex vivo lung perfusion (EVLP) as an optimal platform for donor lung MSC delivery, as well as how the therapeutic potential of MSCs could be further leveraged with genetic engineering. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells in Regenerative Medicine)
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17 pages, 691 KiB  
Review
Managing the Heterogeneity of Mesenchymal Stem Cells for Cartilage Regenerative Therapy: A Review
by Doreen Goh, Yanmeng Yang, Eng Hin Lee, James Hoi Po Hui and Zheng Yang
Bioengineering 2023, 10(3), 355; https://doi.org/10.3390/bioengineering10030355 - 13 Mar 2023
Cited by 6 | Viewed by 2693
Abstract
Articular cartilage defects commonly result from trauma and are associated with significant morbidity. Since cartilage is an avascular, aneural, and alymphatic tissue with a poor intrinsic healing ability, the regeneration of functional hyaline cartilage remains a difficult clinical problem. Mesenchymal stem cells (MSCs) [...] Read more.
Articular cartilage defects commonly result from trauma and are associated with significant morbidity. Since cartilage is an avascular, aneural, and alymphatic tissue with a poor intrinsic healing ability, the regeneration of functional hyaline cartilage remains a difficult clinical problem. Mesenchymal stem cells (MSCs) are multipotent cells with multilineage differentiation potential, including the ability to differentiate into chondrocytes. Due to their availability and ease of ex vivo expansion, clinicians are increasingly applying MSCs in the treatment of cartilage lesions. However, despite encouraging pre-clinical and clinical data, inconsistencies in MSC proliferative and chondrogenic potential depending on donor, tissue source, cell subset, culture conditions, and handling techniques remain a key barrier to widespread clinical application of MSC therapy in cartilage regeneration. In this review, we highlight the strategies to manage the heterogeneity of MSCs ex vivo for more effective cartilage repair, including reducing the MSC culture expansion period, and selecting MSCs with higher chondrogenic potential through specific genetic markers, surface markers, and biophysical attributes. The accomplishment of a less heterogeneous population of culture-expanded MSCs may improve the scalability, reproducibility, and standardisation of MSC therapy for clinical application in cartilage regeneration. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells in Regenerative Medicine)
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29 pages, 1758 KiB  
Review
From Promise to Reality: Bioengineering Strategies to Enhance the Therapeutic Potential of Extracellular Vesicles
by Miguel de Almeida Fuzeta, Pedro P. Gonçalves, Ana Fernandes-Platzgummer, Joaquim M. S. Cabral, Nuno Bernardes and Cláudia L. da Silva
Bioengineering 2022, 9(11), 675; https://doi.org/10.3390/bioengineering9110675 - 10 Nov 2022
Cited by 7 | Viewed by 3288
Abstract
Extracellular vesicles (EVs) have been the focus of great attention over the last decade, considering their promising application as next-generation therapeutics. EVs have emerged as relevant mediators of intercellular communication, being associated with multiple physiological processes, but also in the pathogenesis of several [...] Read more.
Extracellular vesicles (EVs) have been the focus of great attention over the last decade, considering their promising application as next-generation therapeutics. EVs have emerged as relevant mediators of intercellular communication, being associated with multiple physiological processes, but also in the pathogenesis of several diseases. Given their natural ability to shuttle messages between cells, EVs have been explored both as inherent therapeutics in regenerative medicine and as drug delivery vehicles targeting multiple diseases. However, bioengineering strategies are required to harness the full potential of EVs for therapeutic use. For that purpose, a good understanding of EV biology, from their biogenesis to the way they are able to shuttle messages and establish interactions with recipient cells, is needed. Here, we review the current state-of-the-art on EV biology, complemented by representative examples of EVs roles in several pathophysiological processes, as well as the intrinsic therapeutic properties of EVs and paradigmatic strategies to produce and develop engineered EVs as next-generation drug delivery systems. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells in Regenerative Medicine)
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