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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (31 March 2019) | Viewed by 112779

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Prof. Dr. Yong Li

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Chief of BioMedical Engineering, Department of Orthopaedic Surgery, Homer Stryker M.D. School of Medicine, Western Michigan University Kalamazoo, MI 49008, USA
Interests: stem cell; regenerative medicine; fibrosis and cascade; wound healing
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Special Issue Information

Dear Colleagues,

In the last decade, personalized medicine has gained a lot of traction and has pushed the limits of what we can do clinically. The first generation of personalized medicine employed individual analysis of a patient’s unique biology to select more efficacious diagnostic methods and/or suggest clinical treatments. The focus was on identifying genetic factors to assist with selecting treatments, personalizing screens or diagnoses, and honing detection of potential diseases. Currently, these applications offer routine clinical services for patients. Subsequently, personalized medicine has progressed into fields such as gene therapy, cancer treatment, and surgical treatment/design. However, the true potential of personalized medicine, extending well beyond these current applications, waits to be fully realized.

Most disease, trauma, and infectious pathologies are consequences of cellular damage at differing levels. The key to the mitigating cell and/or tissue damage repair needs cell therapy. Stem cell therapy is a promising treatment that can be tailored not only to an illness but also to an individual patient. The potential of stem cell therapy includes a futuristic personalized “medication” in the event of tissue damage secondary to surgeries, toxins, trauma, aging, complications from medication, autoimmune disease, and numerous other problems limited by current medicine. Autologous cell sources are the first priority for cell therapy since they are safe, do not violate ethical perspectives and do not provoke immunogenic responses. Among the various autologous cell sources, induced pluripotent stem cells (iPSCs) show great potential for cell therapy application. In addition to directly treating patient tissue, iPSCs are also inducible into specialized disease cells for quick, easy, and personalized drug testing and dose selecting.

Personalized medicine through stem cell therapy has many benefits that are essential for the future of personal health. The current Special Issue will accept studies and reviews in all fields of personalized medicine. Stem cell-related studies on basic science and translational application in personalized medicine will be welcomed. The goal of this issue is to provide an overview of novel studies, as well as updated classical studies, in personalized medicine.

Prof. Yong Li
Guest Editor

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Keywords

Personalized medicine
Stem cells
Induced pluripotent stem cells (iPSCs)
Genetic identification
Diagnosis
Drug testing

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Published Papers (12 papers)

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Research

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16 pages, 5035 KiB

Open AccessArticle

Peripheral Delivery of Neural Precursor Cells Ameliorates Parkinson’s Disease-Associated Pathology

by George Edwards III, Nazaret Gamez, Enrique Armijo, Carlos Kramm, Rodrigo Morales, Kathleen Taylor-Presse, Paul E. Schulz, Claudio Soto and Ines Moreno-Gonzalez

Cells 2019, 8(11), 1359; https://doi.org/10.3390/cells8111359 - 30 Oct 2019

Cited by 5 | Viewed by 3619

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by loss of motor control due to a wide loss of dopaminergic neurons along the nigro-striatal pathway. Some of the mechanisms that contribute to this cell death are inflammation, oxidative stress, and misfolded alpha-synuclein-induced toxicity. Current treatments are effective at managing the early motor symptoms of the disease, but they become ineffective over time and lead to adverse effects. Previous research using intracerebral stem cell therapy for treatment of PD has provided promising results; however, this method is very invasive and is often associated with unacceptable side effects. In this study, we used an MPTP-injected mouse model of PD and intravenously administered neural precursors (NPs) obtained from mouse embryonic and mesenchymal stem cells. Clinical signs and neuropathology were assessed. Female mice treated with NPs had improved motor function and reduction in the neuroinflammatory response. In terms of safety, there were no tumorigenic formations or any detectable adverse effect after treatment. Our results suggest that peripheral administration of stem cell-derived NPs may be a promising and safe therapy for the recovery of impaired motor function and amelioration of brain pathology in PD. Full article

(This article belongs to the Special Issue Stem Cells in Personalized Medicine)

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16 pages, 2731 KiB

Open AccessArticle

Pooling of Patient-Derived Mesenchymal Stromal Cells Reduces Inter-Individual Confounder-Associated Variation without Negative Impact on Cell Viability, Proliferation and Osteogenic Differentiation

by Benedikt Widholz, Stefanos Tsitlakidis, Bruno Reible, Arash Moghaddam and Fabian Westhauser

Cells 2019, 8(6), 633; https://doi.org/10.3390/cells8060633 - 24 Jun 2019

Cited by 59 | Viewed by 5664

Abstract

Patient-derived mesenchymal stromal cells (MSCs) play a key role in bone tissue engineering. Various donor-specific factors were identified causing significant variability in the biological properties of MSCs impairing quality of data and inter-study comparability. These limitations might be overcome by pooling cells of different donors. However, the effects of pooling on osteogenic differentiation, proliferation and vitality remain unknown and have, therefore, been evaluated in this study. MSCs of 10 donors were cultivated and differentiated into osteogenic lineage individually and in a pooled setting, containing MSCs of each donor in equal parts. Proliferation was evaluated in expansion (assessment of generation time) and differentiation (quantification of dsDNA content) conditions. Vitality was visualized by a fluorescence-microscopy-based live/dead assay. Osteogenic differentiation was assessed by quantification of alkaline phosphatase (ALP) activity and extracellular calcium deposition. Compared to the individual setting, generation time of pooled MSCs was shorter and proliferation was increased during differentiation with significantly lower variances. Calcium deposition was comparable, while variances were significantly higher in the individual setting. ALP activity showed high variance in both groups, but increased comparably during the incubation period. In conclusion, MSC pooling helps to compensate donor-dependent variability and does not negatively influence MSC vitality, proliferation and osteogenic differentiation. Full article

(This article belongs to the Special Issue Stem Cells in Personalized Medicine)

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12 pages, 3702 KiB

Open AccessEditor’s ChoiceArticle

A Cleared View on Retinal Organoids

by Virginia Cora, Jasmin Haderspeck, Lena Antkowiak, Ulrich Mattheus, Peter H. Neckel, Andreas F. Mack, Sylvia Bolz, Marius Ueffing, Natalia Pashkovskaia, Kevin Achberger and Stefan Liebau

Cells 2019, 8(5), 391; https://doi.org/10.3390/cells8050391 - 28 Apr 2019

Cited by 38 | Viewed by 9326

Abstract

Human induced pluripotent stem cell (hiPSC)-derived organoids mimicking tissues and organs in vitro have advanced medical research, as they opened up new possibilities for in-depth basic research on human organ development as well as providing a human in vitro model for personalized therapeutic approaches. hiPSC-derived retinal organoids have proven to be of great value for modeling the human retina featuring a very similar cellular composition, layering, and functionality. The technically challenging imaging of three-dimensional structures such as retinal organoids has, however, raised the need for robust whole-organoid imaging techniques. To improve imaging of retinal organoids we optimized a passive clearing technique (PACT), which enables high-resolution visualization of fragile intra-tissue structures. Using cleared retinal organoids, we could greatly enhance the antibody labeling efficiency and depth of imaging at high resolution, thereby improving the three-dimensional microscopy output. In that course, we were able to identify the spatial morphological shape and organization of, e.g., photoreceptor cells and bipolar cell layers. Moreover, we used the synaptic protein CtBP2/Ribeye to visualize the interconnection points of photoreceptor and bipolar cells forming the retinal-specific ribbon synapses. Full article

(This article belongs to the Special Issue Stem Cells in Personalized Medicine)

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22 pages, 6183 KiB

Open AccessArticle

Exogenous Cytokine-Free Differentiation of Human Pluripotent Stem Cells into Classical Brown Adipocytes

by Masako Oka, Norihiko Kobayashi, Kazunori Matsumura, Miwako Nishio and Kumiko Saeki

Cells 2019, 8(4), 373; https://doi.org/10.3390/cells8040373 - 24 Apr 2019

Cited by 11 | Viewed by 5789

Abstract

We previously established a method for a directed differentiation of human pluripotent stem cells into classical brown adipocytes (BA) by forming aggregates via massive floating culture in the presence of a specific cytokine cocktail. However, use of recombinant cytokines requires significant cost. Moreover, an enforced differentiation by exogenously added cytokines may amend skewed differentiation propensity of patient’s pluripotent stem cells, providing unsatisfactory disease models. Therefore, an exogenous cytokine-free method, where cytokines required for differentiation are provided in an auto/paracrine manner mimicking natural developmental process, is beneficial. Here we show that, if human pluripotent stem cells are cultured as size-controlled spheroids (100–120 µm radius, 2000–2500 cells/spheroid) in a mutually segregated manner with half-change of the medium every other day, they differentiate into classical BA via an authentic MYF5-positive myoblast route in the absence of exogenous cytokines. Differentiated BA exerted thermogenic activity in transplanted mice in response to beta-adrenergic receptor agonist stimuli. The cytokine-free differentiation method has further advantages in exploring BATokines, BA-derived physiologically active substances. Indeed, we have found that BA produces an unknown small (<1000 Da), highly hydrophilic molecule that augments insulin secretion from pancreatic beta cells. Our upgraded technique will contribute to an advancement of stem cell study for diverse purposes. Full article

(This article belongs to the Special Issue Stem Cells in Personalized Medicine)

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17 pages, 3579 KiB

Open AccessArticle

Insights into Inflammatory Priming of Adipose-Derived Mesenchymal Stem Cells: Validation of Extracellular Vesicles-Embedded miRNA Reference Genes as A Crucial Step for Donor Selection

by Enrico Ragni, Paola De Luca, Carlotta Perucca Orfei, Alessandra Colombini, Marco Viganò, Gaia Lugano, Valentina Bollati and Laura de Girolamo

Cells 2019, 8(4), 369; https://doi.org/10.3390/cells8040369 - 23 Apr 2019

Cited by 22 | Viewed by 5296

Abstract

Mesenchymal stem cells (MSCs) are promising tools for cell-based therapies due to their homing to injury sites, where they secrete bioactive factors such as cytokines, lipids, and nucleic acids, either free or conveyed within extracellular vesicles (EVs). Depending on the local environment, MSCs’ therapeutic value may be modulated, determining their fate and cell behavior. Inflammatory signals may induce critical changes on both the phenotype and secretory portfolio. Intriguingly, in animal models resembling joint diseases as osteoarthritis (OA), inflammatory priming enhanced the healing capacity of MSC-derived EVs. In this work, we selected miRNA reference genes (RGs) from the literature (let-7a-5p, miR-16-5p, miR-23a-3p, miR-26a-5p, miR-101-3p, miR-103a-3p, miR-221-3p, miR-423-5p, miR-425-5p, U6 snRNA), using EVs isolated from adipose-derived MSCs (ASCs) primed with IFNγ (iASCs). geNorm, NormFinder, BestKeeper, and ΔCt methods identified miR-26a-5p/16-5p as the most stable, while miR-103a-rp/425-5p performed poorly. Our results were validated on miRNAs involved in OA cartilage trophism. Only a proper normalization strategy reliably identified the differences between donors, a critical factor to empower the therapeutic value of future off-the-shelf MSC-EV isolates. In conclusion, the proposed pipeline increases the accuracy of MSC-EVs embedded miRNAs assessment, and help predicting donor variability for precision medicine approaches. Full article

(This article belongs to the Special Issue Stem Cells in Personalized Medicine)

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20 pages, 32131 KiB

Open AccessArticle

Characteristics and Potentiality of Human Adipose-Derived Stem Cells (hASCs) Obtained from Enzymatic Digestion of Fat Graft

by Pietro Gentile, Maria Serena Piccinno and Claudio Calabrese

Cells 2019, 8(3), 282; https://doi.org/10.3390/cells8030282 - 25 Mar 2019

Cited by 70 | Viewed by 5882

Abstract

Human adipose-derived stem cells localize in the stromal-vascular portion, and can be ex vivo isolated using a combination of washing steps and enzymatic digestion. For this study, we undertook a histological evaluation of traditional fat graft compared with fat graft enriched with stromal vascular fraction cells isolated by the Celution™ system to assess the interactions between cells and adipose tissue before the breast injection. In addition, we reported on histological analyses of biopsies derived from fat grafted (traditional or enriched with SVFs) in the breast in order to assess the quality of the adipose tissue, fibrosis and vessels. The hASCs derived from enzymatic digestion were systematically characterized for growth features, phenotype and multi-potent differentiation potential. They fulfill the definition of mesenchymal stem cells, albeit with a higher neural phenotype profile. These cells also express genes that constitute the core circuitry of self-renewal such as OCT4, SOX2, NANOG and neurogenic lineage genes such as NEUROD1, PAX6 and SOX3. Such findings support the hypothesis that hASCs may have a potential usefulness in neurodegenerative conditions. These data can be helpful for the development of new therapeutic approaches in personalized medicine to assess safety and efficacy of the breast reconstruction. Full article

(This article belongs to the Special Issue Stem Cells in Personalized Medicine)

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22 pages, 7725 KiB

Open AccessArticle

Aberrant hiPSCs-Derived from Human Keratinocytes Differentiates into 3D Retinal Organoids that Acquire Mature Photoreceptors

by Rupendra Shrestha, Yao-Tseng Wen, Dah-Ching Ding and Rong-Kung Tsai

Cells 2019, 8(1), 36; https://doi.org/10.3390/cells8010036 - 9 Jan 2019

Cited by 20 | Viewed by 11492

Abstract

Human induced pluripotent stem cell (hiPSC)-derived three-dimensional retinal organoids are a new platform for studying the organoidogenesis. However, recurrent genomic aberration, acquired during generation of hiPSCs, limit its biomedical application and/or aberrant hiPSCs has not been evaluated for generation of differentiated derivatives, such as organoids and retinal pigment epithelium (RPE). In this study, we efficiently differentiated mosaic hiPSCs into retinal organoids containing mature photoreceptors. The feeder-free hiPSCs were generated from the human epidermal keratinocytes that were rapid in process with improved efficiency over several passages and maintained pluripotency. But, hiPSCs were cytogenetically mosaic with normal and abnormal karyotypes, while copy number variation analysis revealed the loss of chromosome 8q. Despite this abnormality, the stepwise differentiation of hiPSCs to form retinal organoids was autonomous and led to neuronal lamination. Furthermore, the use of a Notch inhibitor, DAPT, at an early timepoint from days 29–42 of culture improved the specification of the retinal neuron and the use of retinoic acid at days 70–120 led to the maturation of photoreceptors. hiPSC-derived retinal organoids acquired all subtypes of photoreceptors, such as RHODOPSIN, B-OPSIN and R/G-OPSIN. Additionally, the advanced maturation of photoreceptors was observed, revealing the development of specific sensory cilia and the formation of the outer-segment disc. This report is the first to show that hiPSCs with abnormal chromosomal content are permissive to the generation of three-dimensional retinal organoids. Full article

(This article belongs to the Special Issue Stem Cells in Personalized Medicine)

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22 pages, 7727 KiB

Open AccessArticle

Cytogenetic and Transcriptomic Analysis of Human Endometrial MSC Retaining Proliferative Activity after Sublethal Heat Shock

by Mariia A. Shilina, Tatiana M. Grinchuk, Olga V. Anatskaya, Alexander E. Vinogradov, Larisa L. Alekseenko, Artem U. Elmuratov and Nikolai N. Nikolsky

Cells 2018, 7(11), 184; https://doi.org/10.3390/cells7110184 - 25 Oct 2018

Cited by 11 | Viewed by 6385

Abstract

Temperature is an important exogenous factor capable of leading to irreversible processes in the vital activity of cells. However, the long-term effects of heat shock (HS) on mesenchymal stromal cells (MSC) remain unstudied. We investigated the karyotype and DNA repair drivers and pathways in the human endometrium MSC (eMSC) survived progeny at passage 6 after sublethal heat stress (sublethal heat stress survived progeny (SHS-SP)). G-banding revealed an outbreak of random karyotype instability caused by chromosome breakages and aneuploidy. Molecular karyotyping confirmed the random nature of this instability. Transcriptome analysis found homologous recombination (HR) deficiency that most likely originated from the low thermostability of the AT-rich HR driving genes. SHS-SP protection from transformation is provided presumably by low oncogene expression maintained by tight co-regulation between thermosensitive HR drivers BRCA, ATM, ATR, and RAD51 (decreasing expression after SHS), and oncogenes mTOR, MDM2, KRAS, and EGFR. The cancer-related transcriptomic features previously identified in hTERT transformed MSC in culture were not found in SHS-SP, suggesting no traits of malignancy in them. The entrance of SHS-SP into replicative senescence after 25 passages confirms their mortality and absence of transformation features. Overall, our data indicate that SHS may trigger non-tumorigenic karyotypic instability due to HR deficiency and decrease of oncogene expression in progeny of SHS-survived MSC. These data can be helpful for the development of new therapeutic approaches in personalized medicine. Full article

(This article belongs to the Special Issue Stem Cells in Personalized Medicine)

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Review

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15 pages, 1035 KiB

Open AccessReview

Ex Vivo Expansion of Hematopoietic Stem Cells for Therapeutic Purposes: Lessons from Development and the Niche

by Parisa Tajer, Karin Pike-Overzet, Sagrario Arias, Menzo Havenga and Frank J.T. Staal

Cells 2019, 8(2), 169; https://doi.org/10.3390/cells8020169 - 18 Feb 2019

Cited by 70 | Viewed by 15574

Abstract

Expansion of hematopoietic stem cells (HSCs) for therapeutic purposes has been a “holy grail” in the field for many years. Ex vivo expansion of HSCs can help to overcome material shortage for transplantation purposes and genetic modification protocols. In this review, we summarize improved understanding in blood development, the effect of niche and conservative signaling pathways on HSCs in mice and humans, and also advances in ex vivo culturing protocols of human HSCs with cytokines or small molecule compounds. Different expansion protocols have been tested in clinical trials. However, an optimal condition for ex vivo expansion of human HSCs still has not been found yet. Translating and implementing new findings from basic research (for instance by using genetic modification of human HSCs) into clinical protocols is crucial to improve ex vivo expansion and eventually boost stem cell gene therapy. Full article

(This article belongs to the Special Issue Stem Cells in Personalized Medicine)

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15 pages, 1432 KiB

Open AccessReview

Treatment of Parkinson’s Disease through Personalized Medicine and Induced Pluripotent Stem Cells

by Theo Stoddard-Bennett and Renee Reijo Pera

Cells 2019, 8(1), 26; https://doi.org/10.3390/cells8010026 - 7 Jan 2019

Cited by 82 | Viewed by 22061

Abstract

Parkinson’s Disease (PD) is an intractable disease resulting in localized neurodegeneration of dopaminergic neurons of the substantia nigra pars compacta. Many current therapies of PD can only address the symptoms and not the underlying neurodegeneration of PD. To better understand the pathophysiological condition, researchers continue to seek models that mirror PD’s phenotypic manifestations as closely as possible. Recent advances in the field of cellular reprogramming and personalized medicine now allow for previously unattainable cell therapies and patient-specific modeling of PD using induced pluripotent stem cells (iPSCs). iPSCs can be selectively differentiated into a dopaminergic neuron fate naturally susceptible to neurodegeneration. In iPSC models, unlike other artificially-induced models, endogenous cellular machinery and transcriptional feedback are preserved, a fundamental step in accurately modeling this genetically complex disease. In addition to accurately modeling PD, iPSC lines can also be established with specific genetic risk factors to assess genetic sub-populations’ differing response to treatment. iPS cell lines can then be genetically corrected and subsequently transplanted back into the patient in hopes of re-establishing function. Current techniques focus on iPSCs because they are patient-specific, thereby reducing the risk of immune rejection. The year 2018 marked history as the year that the first human trial for PD iPSC transplantation began in Japan. This form of cell therapy has shown promising results in other model organisms and is currently one of our best options in slowing or even halting the progression of PD. Here, we examine the genetic contributions that have reshaped our understanding of PD, as well as the advantages and applications of iPSCs for modeling disease and personalized therapies. Full article

(This article belongs to the Special Issue Stem Cells in Personalized Medicine)

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14 pages, 236 KiB

Open AccessFeature PaperReview

iPSCs as a Platform for Disease Modeling, Drug Screening, and Personalized Therapy in Muscular Dystrophies

by Jose L. Ortiz-Vitali and Radbod Darabi

Cells 2019, 8(1), 20; https://doi.org/10.3390/cells8010020 - 3 Jan 2019

Cited by 31 | Viewed by 6361

Abstract

Induced pluripotent stem cells (iPSCs) are the foundation of modern stem cell-based regenerative medicine, especially in the case of degenerative disorders, such as muscular dystrophies (MDs). Since their introduction in 2006, many studies have used iPSCs for disease modeling and identification of involved mechanisms, drug screening, as well as gene correction studies. In the case of muscular dystrophies, these studies commenced in 2008 and continue to address important issues, such as defining the main pathologic mechanisms in different types of MDs, drug screening to improve skeletal/cardiac muscle cell survival and to slow down disease progression, and evaluation of the efficiency of different gene correction approaches, such as exon skipping, Transcription activator-like effector nucleases (TALENs), Zinc finger nucleases (ZFNs) and RNA-guided endonuclease Cas9 (CRISPR/Cas9). In the current short review, we have summarized chronological progress of these studies and their key findings along with a perspective on the future road to successful iPSC-based cell therapy for MDs and the potential hurdles in this field. Full article

(This article belongs to the Special Issue Stem Cells in Personalized Medicine)

12 pages, 1249 KiB

Open AccessReview

2D- and 3D-Based Intestinal Stem Cell Cultures for Personalized Medicine

by Yuan Liu and Ye-Guang Chen

Cells 2018, 7(12), 225; https://doi.org/10.3390/cells7120225 - 22 Nov 2018

Cited by 29 | Viewed by 12298

Abstract

Colorectal cancer (CRC) is one of the most common cancers that have high occurrence and death in both males and females. As various factors have been found to contribute to CRC development, personalized therapies are critical for efficient treatment. To achieve this purpose, the establishment of patient-derived tumor models is critical for diagnosis and drug test. The establishment of three-dimensional (3D) organoid cultures and two-dimensional (2D) monolayer cultures of patient-derived epithelial tissues is a breakthrough for expanding living materials for later use. This review provides an overview of the different types of 2D- and 3D-based intestinal stem cell cultures, their potential benefits, and the drawbacks in personalized medicine in treatment of the intestinal disorders. Full article

(This article belongs to the Special Issue Stem Cells in Personalized Medicine)

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