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1
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Saeedi P, Nilchiani LS, Zand B, Hajimirghasemi M, Halabian R. An overview of stem cells and cell products involved in trauma injury. Regen Ther 2025; 29:60-76. [PMID: 40143930 PMCID: PMC11938091 DOI: 10.1016/j.reth.2025.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 02/01/2025] [Accepted: 02/20/2025] [Indexed: 03/28/2025] Open
Abstract
Trauma injuries represent a significant public health burden worldwide, often leading to long-term disability and reduced quality of life. This review provides a comprehensive overview of the therapeutic potential of stem cells and cell products for traumatic injuries. The extraordinary characteristics of stem cells, such as self-renewal and transdifferentiation, make them definitive candidates for tissue regeneration. Mesenchymal stem cells (MSCs), neural stem cells (NSCs), and hematopoietic stem cells (HSCs) have been tested in preclinical studies for treating distinct traumatic injuries. Stem cell mechanisms of action are addressed through paracrine signaling, immunomodulation, differentiation, and neuroprotection. Cell products such as conditioned media, exosomes, and secretomes offer cell-free resources, thereby avoiding the risks of live cell transplantation. Clinical trials have reported many effective outcomes; however, variability exists across trauma types. Some challenges include tumorigenicity, standardized protocols, and regulatory issues. Collaboration and interdisciplinary research are being conducted to harness stem cells and products for trauma treatment. This emerging field is promising for improving patient recovery and quality of life after traumatic injuries.
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Affiliation(s)
- Pardis Saeedi
- Research Center for Health Management in Mass Gathering, Red Crescent Society of the Islamic Republic of Iran, Tehran, Iran
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Leila Sadat Nilchiani
- Department of Molecular and Cell Biology, Faculty of Advanced Sciences and Technology, Islamic Azad University Tehran Medical Sciences, Tehran, Iran
| | - Bita Zand
- Department of Molecular and Cell Biology, Faculty of Advanced Sciences and Technology, Islamic Azad University Tehran Medical Sciences, Tehran, Iran
| | - Maryam Hajimirghasemi
- Department of Internal Medicine, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Raheleh Halabian
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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2
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Jia H, Moore M, Wadhwa M, Burns C. Human iPSC-Derived Endothelial Cells Exhibit Reduced Immunogenicity in Comparison With Human Primary Endothelial Cells. Stem Cells Int 2024; 2024:6153235. [PMID: 39687754 PMCID: PMC11649354 DOI: 10.1155/sci/6153235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 11/07/2024] [Indexed: 12/18/2024] Open
Abstract
Human induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs) have emerged as a promising source of autologous cells with great potential to produce novel cell therapy for ischemic vascular diseases. However, their clinical application still faces numerous challenges including safety concerns such as the potential aberrant immunogenicity derived from the reprogramming process. This study investigated immunological phenotypes of iPSC-ECs by a side-by-side comparison with primary human umbilical vein ECs (HUVECs). Three types of human iPSC-ECs, NIBSC8-EC generated in house and two commercial iPSC-ECs, alongside HUVECs, were examined for surface expression of proteins of immune relevance under resting conditions and after cytokine activation. All iPSC-EC populations failed to express major histocompatibility complex (MHC) Class II on their surface following interferon-gamma (IFN-γ) treatment but showed similar basal and IFN-γ-stimulated expression levels of MHC Class I of HUVECs. Multiple iPSC-ECs also retained constitutive and tumor necrosis factor-alpha (TNF-α)-stimulated expression levels of intercellular adhesion molecule-1 (ICAM-1) like HUVECs. However, TNF-α induced a differential expression of E-selectin and vascular cell adhesion molecule-1 (VCAM-1) on iPSC-ECs. Furthermore, real-time monitoring of proliferation of human peripheral blood mononuclear cells (PBMCs) cocultured on an endothelial monolayer over 5 days showed that iPSC-ECs provoked distinct dynamics of PBMC proliferation, which was generally decreased in alloreactivity and IFN-γ-stimulated proliferation of PBMCs compared with HUVECs. Consistently, in the conventional mixed lymphocyte reaction (MLR), the proliferation of total CD3+ and CD4+ T cells after 5-day cocultures with multiple iPSC-EC populations was largely reduced compared to HUVECs. Last, multiple iPSC-EC cocultures secreted lower levels of proinflammatory cytokines than HUVEC cocultures. Collectively, iPSC-ECs manifested many similarities, but also some disparities with a generally weaker inflammatory immune response than primary ECs, indicating that iPSC-ECs may possibly exhibit hypoimmunogenicity corresponding with less risk of immune rejection in a transplant setting, which is important for safe and effective cell therapies.
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Affiliation(s)
- Haiyan Jia
- Biotherapeutics and Advanced Therapies, Research and Development, Science and Research Group, Medicines and Healthcare Products Regulatory Agency, Blanche Lane, South Mimms, Potters Bar EN6 3QG, Hertfordshire, UK
| | - Melanie Moore
- Therapeutic Reference Materials, Standards Lifecycle, Science and Research Group, Medicines and Healthcare Products Regulatory Agency, Blanche Lane, South Mimms, Potters Bar EN6 3QG, Hertfordshire, UK
| | - Meenu Wadhwa
- Biotherapeutics and Advanced Therapies, Research and Development, Science and Research Group, Medicines and Healthcare Products Regulatory Agency, Blanche Lane, South Mimms, Potters Bar EN6 3QG, Hertfordshire, UK
| | - Chris Burns
- Biotherapeutics and Advanced Therapies, Research and Development, Science and Research Group, Medicines and Healthcare Products Regulatory Agency, Blanche Lane, South Mimms, Potters Bar EN6 3QG, Hertfordshire, UK
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3
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Abusalah MAH, Priyanka, Abd Rahman ENSE, Choudhary OP. Evolving trends in stem cell therapy: an emerging and promising approach against various diseases. Int J Surg 2024; 110:6862-6868. [PMID: 39699861 DOI: 10.1097/js9.0000000000001948] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 07/01/2024] [Indexed: 12/20/2024]
Affiliation(s)
- Mai Abdel Haleem Abusalah
- Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman, Jordan
| | - Priyanka
- Department of Veterinary Microbiology, College of Veterinary Science, Guru Angad Dev Veterinary and Animal Sciences University
| | - Engku Nur Syafirah Engku Abd Rahman
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kota Bharu, Kelantan, Malaysia
| | - Om Prakash Choudhary
- Department of Veterinary Anatomy, College of Veterinary Science, Guru Angad Dev Veterinary and Animal Sciences University, Rampura Phul, Bathinda, Punjab, India
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Hajmousa G, de Almeida RC, Bloks N, Ruiz AR, Bouma M, Slieker R, Kuipers TB, Nelissen RGHH, Ito K, Freund C, Ramos YFM, Meulenbelt I. The role of DNA methylation in chondrogenesis of human iPSCs as a stable marker of cartilage quality. Clin Epigenetics 2024; 16:141. [PMID: 39407288 PMCID: PMC11481477 DOI: 10.1186/s13148-024-01759-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 10/07/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND Lack of insight into factors that determine purity and quality of human iPSC (hiPSC)-derived neo-cartilage precludes applications of this powerful technology toward regenerative solutions in the clinical setting. Here, we set out to generate methylome-wide landscapes of hiPSC-derived neo-cartilages from different tissues-of-origin and integrated transcriptome-wide data to identify dissimilarities in set points of methylation with associated transcription and the respective pathways in which these genes act. METHODS We applied in vitro chondrogenesis using hiPSCs generated from two different tissue sources: skin fibroblasts and articular cartilage. Upon differentiation toward chondrocytes, these are referred to as hFiCs and hCiC, respectively. Genome-wide DNA methylation and RNA sequencing datasets were generated of the hiPSC-derived neo-cartilages, and the epigenetically regulated transcriptome was compared to that of neo-cartilage deposited by human primary articular cartilage (hPAC). RESULTS Methylome-wide landscapes of neo-cartilages of hiPSCs reprogrammed from two different somatic tissues were 85% similar to that of hPACs. By integration of transcriptome-wide data, differences in transcriptionally active CpGs between hCiC relative to hPAC were prioritized. Among the CpG-gene pairs lower expressed in hCiCs relative to hPACs, we identified genes such as MGP, GDF5, and CHAD enriched in closely related pathways and involved in cartilage development that likely mark phenotypic differences in chondrocyte states. Vice versa, among the CpG-gene pairs higher expressed, we identified genes such as KIF1A or NKX2-2 enriched in neurogenic pathways and likely reflecting off target differentiation. CONCLUSIONS We did not find significant variation between the neo-cartilages derived from hiPSCs of different tissue sources, suggesting that application of a robust differentiation protocol such as we applied here is more important as compared to the epigenetic memory of the cells of origin. Results of our study could be further exploited to improve quality, purity, and maturity of hiPSC-derived neo-cartilage matrix, ultimately to realize introduction of sustainable, hiPSC-derived neo-cartilage implantation into clinical practice.
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Affiliation(s)
- Ghazaleh Hajmousa
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Post-zone S-05-P, P.O. Box 9600, 2300 RC, Leiden, The Netherlands
| | - Rodrigo Coutinho de Almeida
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Post-zone S-05-P, P.O. Box 9600, 2300 RC, Leiden, The Netherlands
| | - Niek Bloks
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Post-zone S-05-P, P.O. Box 9600, 2300 RC, Leiden, The Netherlands
| | - Alejandro Rodríguez Ruiz
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Post-zone S-05-P, P.O. Box 9600, 2300 RC, Leiden, The Netherlands
| | - Marga Bouma
- Department of Anatomy and Embryology and Human iPSC Hotel, 2333 ZA, Leiden, The Netherlands
| | - Roderick Slieker
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
| | - Thomas B Kuipers
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
| | - Rob G H H Nelissen
- Department of Orthopedics, Leiden University Medical Center, Leiden, The Netherlands
| | - Keita Ito
- Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, The Netherlands
| | - Christian Freund
- Department of Anatomy and Embryology and Human iPSC Hotel, 2333 ZA, Leiden, The Netherlands
| | - Yolande F M Ramos
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Post-zone S-05-P, P.O. Box 9600, 2300 RC, Leiden, The Netherlands
| | - Ingrid Meulenbelt
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Post-zone S-05-P, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
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5
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Mohite P, Puri A, Dave R, Budar A, Munde S, Ghosh SB, Alqahtani T, Shmrany HA, Kumer A, Dhara B. Unlocking the therapeutic potential: odyssey of induced pluripotent stem cells in precision cell therapies. Int J Surg 2024; 110:6432-6455. [PMID: 38963728 PMCID: PMC11487032 DOI: 10.1097/js9.0000000000001892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 06/17/2024] [Indexed: 07/06/2024]
Abstract
This review explores the application of induced pluripotent stem cells (iPSCs) in regenerative medicine. The therapeutic significance of iPSC-derived cell therapy within regenerative medicine, emphasizes their reprogramming process and crucial role in cellular differentiation while setting the purpose and scope for the comprehensive exploration of iPSC-derived cell therapy. The subsequent sections intricately examine iPSC-derived cell therapy, unraveling the diverse derivatives of iPSCs and striking a delicate balance between advantages and limitations in therapeutic applications. Mechanisms of action, revealing how iPSC-derived cells seamlessly integrate into tissues, induce regeneration, and contribute to disease modeling and drug screening advancements is discussed. The analysis extends to clinical trials, shedding light on outcomes, safety considerations, and ethical dimensions. Challenges and concerns, including the risk of tumorigenesis and scalability issues, are explored. The focus extends to disease-specific applications, showcasing iPSC-derived cell therapy as a promising avenue for various medical conditions, supported by illustrative case studies. Future directions and research needs are outlined, identifying areas for further exploration, safety considerations and potential enhancements that will shape the future landscape of iPSC-derived therapies. In conclusion, this review provides a significant understanding of iPSC-derived cell therapy's status that contemplates the implications for regenerative medicine and personalized treatment using iPSCs, offering a comprehensive perspective on the evolving field within the confines of a dynamic and promising scientific frontier.
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Affiliation(s)
- Popat Mohite
- AETs St. John Institute of Pharmacy and Research, Palghar, Maharashtra
| | - Abhijeet Puri
- AETs St. John Institute of Pharmacy and Research, Palghar, Maharashtra
| | - Roshan Dave
- AETs St. John Institute of Pharmacy and Research, Palghar, Maharashtra
| | - Aarati Budar
- AETs St. John Institute of Pharmacy and Research, Palghar, Maharashtra
| | - Shubham Munde
- AETs St. John Institute of Pharmacy and Research, Palghar, Maharashtra
| | - Shruti Bagchi Ghosh
- Department of Pharmaceutical Chemistry, Calcutta Institute of Pharmaceutical Technology and Allied Health Science, Uluberia, Howrah
| | - Taha Alqahtani
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha
| | - Humood Al Shmrany
- Department of Medical Laboratory Sciences, College of Applied medical sciences, Prince Sattam bin Abdulaziz University, Alkharj, Saudi Arabia
| | - Ajoy Kumer
- Department of Chemistry, IUBAT-International University of Business Agriculture & Technology, Dhaka, Bangladesh
| | - Bikram Dhara
- Center for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Chennai, India
- Department of Health Sciences, Novel Global Community and Educational Foundation. Hebersham, NSW, Australia
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6
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Eivazi Zadeh Z, Nour S, Kianersi S, Jonidi Shariatzadeh F, Williams RJ, Nisbet DR, Bruggeman KF. Mining human clinical waste as a rich source of stem cells for neural regeneration. iScience 2024; 27:110307. [PMID: 39156636 PMCID: PMC11326931 DOI: 10.1016/j.isci.2024.110307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/20/2024] Open
Abstract
Neural diseases are challenging to treat and are regarded as one of the major causes of disability and morbidity in the world. Stem cells can provide a solution, by offering a mechanism to replace damaged circuitry. However, obtaining sufficient cell sources for neural regeneration remains a significant challenge. In recent years, waste-derived stem(-like) cells (WDS-lCs) extracted from both prenatal and adult clinical waste tissues/products, have gained increasing attention for application in neural tissue repair and remodeling. This often-overlooked pool of cells possesses favorable characteristics; including self-renewal, neural differentiation, secretion of neurogenic factors, cost-effectiveness, and low ethical concerns. Here, we offer a perspective regarding the biological properties, extraction protocols, and preclinical and clinical treatments where prenatal and adult WDS-lCs have been utilized for cell replacement therapy in neural applications, and the challenges involved in optimizing these approaches toward patient led therapies.
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Affiliation(s)
- Zahra Eivazi Zadeh
- Department of Biomedical Engineering, University of Melbourne, Parkville, VIC 3010, Australia
- The Graeme Clark Institute, University of Melbourne, Melbourne, VIC, Australia
| | - Shirin Nour
- Department of Biomedical Engineering, University of Melbourne, Parkville, VIC 3010, Australia
- The Graeme Clark Institute, University of Melbourne, Melbourne, VIC, Australia
- Polymer Science Group, Department of Chemical Engineering, University of Melbourne, Parkville, VIC 3010, Australia
| | - Sogol Kianersi
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences, University of Galway, Galway, Ireland
| | | | - Richard J. Williams
- The Graeme Clark Institute, University of Melbourne, Melbourne, VIC, Australia
- iMPACT, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia
| | - David R. Nisbet
- Department of Biomedical Engineering, University of Melbourne, Parkville, VIC 3010, Australia
- The Graeme Clark Institute, University of Melbourne, Melbourne, VIC, Australia
- ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, ANU College of Health & Medicine, Canberra, ACT, Australia
- Research School of Chemistry, ANU College of Science, Canberra, ACT, Australia
- Melbourne Medical School, Faculty of Medicine, Dentistry and Health Science, The University of Melbourne, Melbourne, VIC, Australia
- Founder and Scientific Advisory of Nano Status, Building 137, Sullivans Creek Rd, ANU, Acton, Canberra, ACT, Australia
| | - Kiara F. Bruggeman
- Laboratory of Advanced Biomaterials Research, School of Engineering, Australian National University, Canberra, ACT, Australia
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7
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Lin Y, Sato N, Hong S, Nakamura K, Ferrante EA, Yu ZX, Chen MY, Nakamura DS, Yang X, Clevenger RR, Hunt TJ, Taylor JL, Jeffries KR, Keeran KJ, Neidig LE, Mehta A, Schwartzbeck R, Yu SJ, Kelly C, Navarengom K, Takeda K, Adler SS, Choyke PL, Zou J, Murry CE, Boehm M, Dunbar CE. Long-term engraftment and maturation of autologous iPSC-derived cardiomyocytes in two rhesus macaques. Cell Stem Cell 2024; 31:974-988.e5. [PMID: 38843830 PMCID: PMC11227404 DOI: 10.1016/j.stem.2024.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 03/14/2024] [Accepted: 05/10/2024] [Indexed: 07/08/2024]
Abstract
Cellular therapies with cardiomyocytes produced from induced pluripotent stem cells (iPSC-CMs) offer a potential route to cardiac regeneration as a treatment for chronic ischemic heart disease. Here, we report successful long-term engraftment and in vivo maturation of autologous iPSC-CMs in two rhesus macaques with small, subclinical chronic myocardial infarctions, all without immunosuppression. Longitudinal positron emission tomography imaging using the sodium/iodide symporter (NIS) reporter gene revealed stable grafts for over 6 and 12 months, with no teratoma formation. Histological analyses suggested capability of the transplanted iPSC-CMs to mature and integrate with endogenous myocardium, with no sign of immune cell infiltration or rejection. By contrast, allogeneic iPSC-CMs were rejected within 8 weeks of transplantation. This study provides the longest-term safety and maturation data to date in any large animal model, addresses concerns regarding neoantigen immunoreactivity of autologous iPSC therapies, and suggests that autologous iPSC-CMs would similarly engraft and mature in human hearts.
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Affiliation(s)
- Yongshun Lin
- iPSC Core, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Noriko Sato
- Laboratory of Cellular Therapeutics, Molecular Imaging Branch, National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA
| | - Sogun Hong
- Translational Stem Cell Biology Branch, NHLBI, NIH, Bethesda, MD 20892, USA
| | - Kenta Nakamura
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA; Department of Medicine/Cardiology, University of Washington, Seattle, WA 98195, USA
| | - Elisa A Ferrante
- Translational Vascular Medicine Branch, NHLBI, NIH, Bethesda, MD 20892, USA
| | - Zu Xi Yu
- Pathology Core, NHLBI, NIH, Bethesda, MD 20892, USA
| | - Marcus Y Chen
- Cardiovascular Branch, NHLBI, NIH, Bethesda, MD 20892, USA
| | - Daisy S Nakamura
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA; Department of Medicine/Cardiology, University of Washington, Seattle, WA 98195, USA
| | - Xiulan Yang
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA; Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA
| | | | - Timothy J Hunt
- Animal Surgery and Resources Core, NHLBI, NIH, Bethesda, MD 20892, USA
| | - Joni L Taylor
- Animal Surgery and Resources Core, NHLBI, NIH, Bethesda, MD 20892, USA
| | | | - Karen J Keeran
- Animal Surgery and Resources Core, NHLBI, NIH, Bethesda, MD 20892, USA
| | - Lauren E Neidig
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA; Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA
| | - Atul Mehta
- Translational Vascular Medicine Branch, NHLBI, NIH, Bethesda, MD 20892, USA
| | - Robin Schwartzbeck
- Translational Vascular Medicine Branch, NHLBI, NIH, Bethesda, MD 20892, USA
| | - Shiqin Judy Yu
- Translational Stem Cell Biology Branch, NHLBI, NIH, Bethesda, MD 20892, USA
| | - Conor Kelly
- Translational Stem Cell Biology Branch, NHLBI, NIH, Bethesda, MD 20892, USA
| | - Keron Navarengom
- Translational Vascular Medicine Branch, NHLBI, NIH, Bethesda, MD 20892, USA
| | - Kazuyo Takeda
- Microscopy and Imaging Core, CBER, FDA, Silver Spring, MD, USA
| | - Stephen S Adler
- Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Peter L Choyke
- Laboratory of Cellular Therapeutics, Molecular Imaging Branch, National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA
| | - Jizhong Zou
- iPSC Core, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Charles E Murry
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA; Department of Medicine/Cardiology, University of Washington, Seattle, WA 98195, USA; Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Bioengineering, University of Washington School of Medicine, Seattle, WA 98195, USA.
| | - Manfred Boehm
- Translational Vascular Medicine Branch, NHLBI, NIH, Bethesda, MD 20892, USA.
| | - Cynthia E Dunbar
- Translational Stem Cell Biology Branch, NHLBI, NIH, Bethesda, MD 20892, USA.
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8
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Park TY, Jeon J, Cha Y, Kim KS. Past, present, and future of cell replacement therapy for parkinson's disease: a novel emphasis on host immune responses. Cell Res 2024; 34:479-492. [PMID: 38777859 PMCID: PMC11217403 DOI: 10.1038/s41422-024-00971-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 04/28/2024] [Indexed: 05/25/2024] Open
Abstract
Parkinson's disease (PD) stands as the second most common neurodegenerative disorder after Alzheimer's disease, and its prevalence continues to rise with the aging global population. Central to the pathophysiology of PD is the specific degeneration of midbrain dopamine neurons (mDANs) in the substantia nigra. Consequently, cell replacement therapy (CRT) has emerged as a promising treatment approach, initially supported by various open-label clinical studies employing fetal ventral mesencephalic (fVM) cells. Despite the initial favorable results, fVM cell therapy has intrinsic and logistical limitations that hinder its transition to a standard treatment for PD. Recent efforts in the field of cell therapy have shifted its focus towards the utilization of human pluripotent stem cells, including human embryonic stem cells and induced pluripotent stem cells, to surmount existing challenges. However, regardless of the transplantable cell sources (e.g., xenogeneic, allogeneic, or autologous), the poor and variable survival of implanted dopamine cells remains a major obstacle. Emerging evidence highlights the pivotal role of host immune responses following transplantation in influencing the survival of implanted mDANs, underscoring an important area for further research. In this comprehensive review, building upon insights derived from previous fVM transplantation studies, we delve into the functional ramifications of host immune responses on the survival and efficacy of grafted dopamine cells. Furthermore, we explore potential strategic approaches to modulate the host immune response, ultimately aiming for optimal outcomes in future clinical applications of CRT for PD.
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Affiliation(s)
- Tae-Yoon Park
- Molecular Neurobiology Laboratory, Department of Psychiatry and McLean Hospital, Harvard Medical School, Belmont, MA, USA
- Program in Neuroscience, Harvard Medical School, Belmont, MA, USA
| | - Jeha Jeon
- Molecular Neurobiology Laboratory, Department of Psychiatry and McLean Hospital, Harvard Medical School, Belmont, MA, USA
- Program in Neuroscience, Harvard Medical School, Belmont, MA, USA
| | - Young Cha
- Molecular Neurobiology Laboratory, Department of Psychiatry and McLean Hospital, Harvard Medical School, Belmont, MA, USA
- Program in Neuroscience, Harvard Medical School, Belmont, MA, USA
| | - Kwang-Soo Kim
- Molecular Neurobiology Laboratory, Department of Psychiatry and McLean Hospital, Harvard Medical School, Belmont, MA, USA.
- Program in Neuroscience, Harvard Medical School, Belmont, MA, USA.
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Harvard Stem Cell Institute, Harvard Medical School, Belmont, MA, USA.
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9
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Ali EAM, Smaida R, Meyer M, Ou W, Li Z, Han Z, Benkirane-Jessel N, Gottenberg JE, Hua G. iPSCs chondrogenic differentiation for personalized regenerative medicine: a literature review. Stem Cell Res Ther 2024; 15:185. [PMID: 38926793 PMCID: PMC11210138 DOI: 10.1186/s13287-024-03794-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024] Open
Abstract
Cartilage, an important connective tissue, provides structural support to other body tissues, and serves as a cushion against impacts throughout the body. Found at the end of the bones, cartilage decreases friction and averts bone-on-bone contact during joint movement. Therefore, defects of cartilage can result from natural wear and tear, or from traumatic events, such as injuries or sudden changes in direction during sports activities. Overtime, these cartilage defects which do not always produce immediate symptoms, could lead to severe clinical pathologies. The emergence of induced pluripotent stem cells (iPSCs) has revolutionized the field of regenerative medicine, providing a promising platform for generating various cell types for therapeutic applications. Thus, chondrocytes differentiated from iPSCs become a promising avenue for non-invasive clinical interventions for cartilage injuries and diseases. In this review, we aim to highlight the current strategies used for in vitro chondrogenic differentiation of iPSCs and to explore their multifaceted applications in disease modeling, drug screening, and personalized regenerative medicine. Achieving abundant functional iPSC-derived chondrocytes requires optimization of culture conditions, incorporating specific growth factors, and precise temporal control. Continual improvements in differentiation methods and integration of emerging genome editing, organoids, and 3D bioprinting technologies will enhance the translational applications of iPSC-derived chondrocytes. Finally, to unlock the benefits for patients suffering from cartilage diseases through iPSCs-derived technologies in chondrogenesis, automatic cell therapy manufacturing systems will not only reduce human intervention and ensure sterile processes within isolator-like platforms to minimize contamination risks, but also provide customized production processes with enhanced scalability and efficiency.
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Affiliation(s)
- Eltahir Abdelrazig Mohamed Ali
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1260, Regenerative NanoMedicine (RNM), 1 Rue Eugène Boeckel, 67000, Strasbourg, France
- Université de Strasbourg, 67000, Strasbourg, France
| | - Rana Smaida
- Lamina Therapeutics, 1 Rue Eugène Boeckel, 67000, Strasbourg, France
| | - Morgane Meyer
- Université de Strasbourg, 67000, Strasbourg, France
- Lamina Therapeutics, 1 Rue Eugène Boeckel, 67000, Strasbourg, France
| | - Wenxin Ou
- Université de Strasbourg, 67000, Strasbourg, France
- Centre National de Référence des Maladies Auto-Immunes et Systémiques Rares, Est/Sud-Ouest (RESO), Service de Rhumatologie, Centre Hospitalier Universitaire de Strasbourg, 67000, Strasbourg, France
- Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, China
| | - Zongjin Li
- Nankai University School of Medicine, Tianjin, 300071, China
| | - Zhongchao Han
- Beijing Engineering Laboratory of Perinatal Stem Cells, Beijing Institute of Health and Stem Cells, Health & Biotech Co, Beijing, 100176, China
| | - Nadia Benkirane-Jessel
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1260, Regenerative NanoMedicine (RNM), 1 Rue Eugène Boeckel, 67000, Strasbourg, France.
- Université de Strasbourg, 67000, Strasbourg, France.
- Lamina Therapeutics, 1 Rue Eugène Boeckel, 67000, Strasbourg, France.
| | - Jacques Eric Gottenberg
- Université de Strasbourg, 67000, Strasbourg, France.
- Centre National de Référence des Maladies Auto-Immunes et Systémiques Rares, Est/Sud-Ouest (RESO), Service de Rhumatologie, Centre Hospitalier Universitaire de Strasbourg, 67000, Strasbourg, France.
| | - Guoqiang Hua
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1260, Regenerative NanoMedicine (RNM), 1 Rue Eugène Boeckel, 67000, Strasbourg, France.
- Université de Strasbourg, 67000, Strasbourg, France.
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10
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Taherian M, Bayati P, Mojtabavi N. Stem cell-based therapy for fibrotic diseases: mechanisms and pathways. Stem Cell Res Ther 2024; 15:170. [PMID: 38886859 PMCID: PMC11184790 DOI: 10.1186/s13287-024-03782-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 06/04/2024] [Indexed: 06/20/2024] Open
Abstract
Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is categorized under the term organ failure could affect various organs in different situations. The involvement of the major organs, such as the lungs, liver, kidney, heart, and skin, is associated with a high rate of morbidity and mortality across the world. Fibrotic disorders encompass a broad range of complications and could be traced to various illnesses and impairments; these could range from simple skin scars with beauty issues to severe rheumatologic or inflammatory disorders such as systemic sclerosis as well as idiopathic pulmonary fibrosis. Besides, the overactivation of immune responses during any inflammatory condition causing tissue damage could contribute to the pathogenic fibrotic events accompanying the healing response; for instance, the inflammation resulting from tissue engraftment could cause the formation of fibrotic scars in the grafted tissue, even in cases where the immune system deals with hard to clear infections, fibrotic scars could follow and cause severe adverse effects. A good example of such a complication is post-Covid19 lung fibrosis which could impair the life of the affected individuals with extensive lung involvement. However, effective therapies that halt or slow down the progression of fibrosis are missing in the current clinical settings. Considering the immunomodulatory and regenerative potential of distinct stem cell types, their application as an anti-fibrotic agent, capable of attenuating tissue fibrosis has been investigated by many researchers. Although the majority of the studies addressing the anti-fibrotic effects of stem cells indicated their potent capabilities, the underlying mechanisms, and pathways by which these cells could impact fibrotic processes remain poorly understood. Here, we first, review the properties of various stem cell types utilized so far as anti-fibrotic treatments and discuss the challenges and limitations associated with their applications in clinical settings; then, we will summarize the general and organ-specific mechanisms and pathways contributing to tissue fibrosis; finally, we will describe the mechanisms and pathways considered to be employed by distinct stem cell types for exerting anti-fibrotic events.
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Affiliation(s)
- Marjan Taherian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Paria Bayati
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nazanin Mojtabavi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
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11
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Moyo MTG, Adali T, Tulay P. Exploring gellan gum-based hydrogels for regenerating human embryonic stem cells in age-related macular degeneration therapy: A literature review. Regen Ther 2024; 26:235-250. [PMID: 38966602 PMCID: PMC11222715 DOI: 10.1016/j.reth.2024.05.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 05/15/2024] [Accepted: 05/26/2024] [Indexed: 07/06/2024] Open
Abstract
Age-related macular degeneration (AMD) is a progressive ocular disease marked by the deterioration of retinal photoreceptor cells, leading to central vision decline, predominantly affecting the elderly population worldwide. Current treatment modalities, such as anti-VEGF agents, laser therapy, and photodynamic therapy, aim to manage the condition, with emerging strategies like stem cell replacement therapy showing promise. However, challenges like immune rejection and cell survival hinder the efficacy of stem cell interventions. Regenerative medicine faces obstacles in maximizing stem cell potential due to limitations in mimicking the dynamic cues of the extracellular matrix (ECM) crucial for guiding stem cell behaviour. Innovative biomaterials like gellan gum hydrogels offer tailored microenvironments conducive to enhancing stem cell culture efficacy and tissue regeneration. Gellan gum-based hydrogels, renowned for biocompatibility and customizable mechanical properties, provide crucial support for cell viability, differentiation, and controlled release of therapeutic factors, making them an ideal platform for culturing human embryonic stem cells (hESCs). These hydrogels mimic native tissue mechanics, promoting optimal hESC differentiation while minimizing immune responses and facilitating localized delivery. This review explores the potential of Gellan Gum-Based Hydrogels in regenerative AMD therapy, emphasizing their role in enhancing hESC regeneration and addressing current status, treatment limitations, and future directions.
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Affiliation(s)
- Mthabisi Talent George Moyo
- Near East University, Faculty of Engineering, Department of Biomedical Engineering, P.O. Box: 99138, Nicosia, Cyprus, Mersin 10, Turkey
- Girne American University, Faculty of Medicine, Department of Medical Biochemistry, PO Box 99428, Karmi Campus, Karaoglanoglu, Kyrenia, Cyprus, Mersin 10, Turkey
- Girne American University, Research and Application Center of Biomedical Sciences, PO Box 99428, Karmi Campus, Karaoglanoglu, Kyrenia, North Cyprus, Mersin 10, Turkey
| | - Terin Adali
- Girne American University, Faculty of Medicine, Department of Medical Biochemistry, PO Box 99428, Karmi Campus, Karaoglanoglu, Kyrenia, Cyprus, Mersin 10, Turkey
- Girne American University, Research and Application Center of Biomedical Sciences, PO Box 99428, Karmi Campus, Karaoglanoglu, Kyrenia, North Cyprus, Mersin 10, Turkey
| | - Pinar Tulay
- Near East University, Faculty of Medicine, Department of Medical Genetics, Nicosia, Cyprus, Mersin 10, Turkey
- Near East University, DESAM Research Institute, Nicosia, Cyprus, Mersin 10, Turkey
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12
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Bogomiakova ME, Bogomazova AN, Lagarkova MA. Dysregulation of Immune Tolerance to Autologous iPSCs and Their Differentiated Derivatives. BIOCHEMISTRY. BIOKHIMIIA 2024; 89:799-816. [PMID: 38880643 DOI: 10.1134/s0006297924050031] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 12/21/2023] [Accepted: 02/13/2024] [Indexed: 06/18/2024]
Abstract
Induced pluripotent stem cells (iPSCs), capable of differentiating into any cell type, are a promising tool for solving the problem of donor organ shortage. In addition, reprogramming technology makes it possible to obtain a personalized, i.e., patient-specific, cell product transplantation of which should not cause problems related to histocompatibility of the transplanted tissues and organs. At the same time, inconsistent information about the main advantage of autologous iPSC-derivatives - lack of immunogenicity - still casts doubt on the possibility of using such cells beyond immunosuppressive therapy protocols. This review is devoted to immunogenic properties of the syngeneic and autologous iPSCs and their derivatives, as well as to the reasons for dysregulation of their immune tolerance.
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Affiliation(s)
- Margarita E Bogomiakova
- Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency, Moscow, 119435, Russia.
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency, Moscow, 119435, Russia
| | - Alexandra N Bogomazova
- Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency, Moscow, 119435, Russia
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency, Moscow, 119435, Russia
| | - Maria A Lagarkova
- Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency, Moscow, 119435, Russia
- Lomonosov Moscow State University, Moscow, 119991, Russia
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13
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Ho BX, Teo AKK, Ng NHJ. Innovations in bio-engineering and cell-based approaches to address immunological challenges in islet transplantation. Front Immunol 2024; 15:1375177. [PMID: 38650946 PMCID: PMC11033429 DOI: 10.3389/fimmu.2024.1375177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 03/11/2024] [Indexed: 04/25/2024] Open
Abstract
Human allogeneic pancreatic islet transplantation is a life-changing treatment for patients with severe Type 1 Diabetes (T1D) who suffer from hypoglycemia unawareness and high risk of severe hypoglycemia. However, intensive immunosuppression is required to prevent immune rejection of the graft, that may in turn lead to undesirable side effects such as toxicity to the islet cells, kidney toxicity, occurrence of opportunistic infections, and malignancies. The shortage of cadaveric human islet donors further limits islet transplantation as a treatment option for widespread adoption. Alternatively, porcine islets have been considered as another source of insulin-secreting cells for transplantation in T1D patients, though xeno-transplants raise concerns over the risk of endogenous retrovirus transmission and immunological incompatibility. As a result, technological advancements have been made to protect transplanted islets from immune rejection and inflammation, ideally in the absence of chronic immunosuppression, to improve the outcomes and accessibility of allogeneic islet cell replacement therapies. These include the use of microencapsulation or macroencapsulation devices designed to provide an immunoprotective environment using a cell-impermeable layer, preventing immune cell attack of the transplanted cells. Other up and coming advancements are based on the use of stem cells as the starting source material for generating islet cells 'on-demand'. These starting stem cell sources include human induced pluripotent stem cells (hiPSCs) that have been genetically engineered to avoid the host immune response, curated HLA-selected donor hiPSCs that can be matched with recipients within a given population, and multipotent stem cells with natural immune privilege properties. These strategies are developed to provide an immune-evasive cell resource for allogeneic cell therapy. This review will summarize the immunological challenges facing islet transplantation and highlight recent bio-engineering and cell-based approaches aimed at avoiding immune rejection, to improve the accessibility of islet cell therapy and enhance treatment outcomes. Better understanding of the different approaches and their limitations can guide future research endeavors towards developing more comprehensive and targeted strategies for creating a more tolerogenic microenvironment, and improve the effectiveness and sustainability of islet transplantation to benefit more patients.
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Affiliation(s)
- Beatrice Xuan Ho
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- BetaLife Pte Ltd, Singapore, Singapore
| | - Adrian Kee Keong Teo
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Precision Medicine Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Natasha Hui Jin Ng
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
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14
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Zhang J, Suo M, Wang J, Liu X, Huang H, Wang K, Liu X, Sun T, Li Z, Liu J. Standardisation is the key to the sustained, rapid and healthy development of stem cell-based therapy. Clin Transl Med 2024; 14:e1646. [PMID: 38572666 PMCID: PMC10993161 DOI: 10.1002/ctm2.1646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 02/20/2024] [Accepted: 03/17/2024] [Indexed: 04/05/2024] Open
Abstract
BACKGROUND Stem cell-based therapy (SCT) is an important component of regenerative therapy that brings hope to many patients. After decades of development, SCT has made significant progress in the research of various diseases, and the market size has also expanded significantly. The transition of SCT from small-scale, customized experiments to routine clinical practice requires the assistance of standards. Many countries and international organizations around the world have developed corresponding SCT standards, which have effectively promoted the further development of the SCT industry. METHODS We conducted a comprehensive literature review to introduce the clinical application progress of SCT and focus on the development status of SCT standardization. RESULTS We first briefly introduced the types and characteristics of stem cells, and summarized the current clinical application and market development of SCT. Subsequently, we focused on the development status of SCT-related standards as of now from three levels: the International Organization for Standardization (ISO), important international organizations, and national organizations. Finally, we provided perspectives and conclusions on the significance and challenges of SCT standardization. CONCLUSIONS Standardization plays an important role in the sustained, rapid and healthy development of SCT.
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Affiliation(s)
- Jing Zhang
- Department of OrthopedicsFirst Affiliated Hospital of Dalian Medical UniversityDalianLiaoning ProvinceChina
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic DiseasesDalianLiaoning ProvinceChina
| | - Moran Suo
- Department of OrthopedicsFirst Affiliated Hospital of Dalian Medical UniversityDalianLiaoning ProvinceChina
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic DiseasesDalianLiaoning ProvinceChina
| | - Jinzuo Wang
- Department of OrthopedicsFirst Affiliated Hospital of Dalian Medical UniversityDalianLiaoning ProvinceChina
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic DiseasesDalianLiaoning ProvinceChina
| | - Xin Liu
- Department of OrthopedicsFirst Affiliated Hospital of Dalian Medical UniversityDalianLiaoning ProvinceChina
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic DiseasesDalianLiaoning ProvinceChina
| | - Huagui Huang
- Department of OrthopedicsFirst Affiliated Hospital of Dalian Medical UniversityDalianLiaoning ProvinceChina
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic DiseasesDalianLiaoning ProvinceChina
| | - Kaizhong Wang
- Department of OrthopedicsFirst Affiliated Hospital of Dalian Medical UniversityDalianLiaoning ProvinceChina
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic DiseasesDalianLiaoning ProvinceChina
| | - Xiangyan Liu
- Department of OrthopedicsFirst Affiliated Hospital of Dalian Medical UniversityDalianLiaoning ProvinceChina
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic DiseasesDalianLiaoning ProvinceChina
| | - Tianze Sun
- Department of OrthopedicsFirst Affiliated Hospital of Dalian Medical UniversityDalianLiaoning ProvinceChina
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic DiseasesDalianLiaoning ProvinceChina
| | - Zhonghai Li
- Department of OrthopedicsFirst Affiliated Hospital of Dalian Medical UniversityDalianLiaoning ProvinceChina
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic DiseasesDalianLiaoning ProvinceChina
- Stem Cell Clinical Research CenterNational Joint Engineering LaboratoryFirst Affiliated Hospital of Dalian Medical UniversityDalianLiaoning ProvinceChina
- Dalian Innovation Institute of Stem Cell and Precision MedicineDalianLiaoning ProvinceChina
| | - Jing Liu
- Stem Cell Clinical Research CenterNational Joint Engineering LaboratoryFirst Affiliated Hospital of Dalian Medical UniversityDalianLiaoning ProvinceChina
- Dalian Innovation Institute of Stem Cell and Precision MedicineDalianLiaoning ProvinceChina
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15
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Hadzimustafic N, D’Elia A, Shamoun V, Haykal S. Human-Induced Pluripotent Stem Cells in Plastic and Reconstructive Surgery. Int J Mol Sci 2024; 25:1863. [PMID: 38339142 PMCID: PMC10855589 DOI: 10.3390/ijms25031863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/25/2024] [Accepted: 02/01/2024] [Indexed: 02/12/2024] Open
Abstract
A hallmark of plastic and reconstructive surgery is restoring form and function. Historically, tissue procured from healthy portions of a patient's body has been used to fill defects, but this is limited by tissue availability. Human-induced pluripotent stem cells (hiPSCs) are stem cells derived from the de-differentiation of mature somatic cells. hiPSCs are of particular interest in plastic surgery as they have the capacity to be re-differentiated into more mature cells, and cultured to grow tissues. This review aims to evaluate the applications of hiPSCs in the plastic surgery context, with a focus on recent advances and limitations. The use of hiPSCs and non-human iPSCs has been researched in the context of skin, nerve, vasculature, skeletal muscle, cartilage, and bone regeneration. hiPSCs offer a future for regenerated autologous skin grafts, flaps comprised of various tissue types, and whole functional units such as the face and limbs. Also, they can be used to model diseases affecting tissues of interest in plastic surgery, such as skin cancers, epidermolysis bullosa, and scleroderma. Tumorigenicity, immunogenicity and pragmatism still pose significant limitations. Further research is required to identify appropriate somatic origin and induction techniques to harness the epigenetic memory of hiPSCs or identify methods to manipulate epigenetic memory.
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Affiliation(s)
- Nina Hadzimustafic
- Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (N.H.); (A.D.); (V.S.)
| | - Andrew D’Elia
- Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (N.H.); (A.D.); (V.S.)
| | - Valentina Shamoun
- Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (N.H.); (A.D.); (V.S.)
| | - Siba Haykal
- Department of Plastic and Reconstructive Surgery, University Health Network, Toronto, ON M5G 2C4, Canada
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16
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Zolfaghari Baghbadorani P, Rayati Damavandi A, Moradi S, Ahmadi M, Bemani P, Aria H, Mottedayyen H, Rayati Damavandi A, Eskandari N, Fathi F. Current advances in stem cell therapy in the treatment of multiple sclerosis. Rev Neurosci 2023; 34:613-633. [PMID: 36496351 DOI: 10.1515/revneuro-2022-0102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 11/18/2022] [Indexed: 08/04/2023]
Abstract
Multiple sclerosis (MS) is an inflammatory disease related to the central nervous system (CNS) with a significant global burden. In this illness, the immune system plays an essential role in its pathophysiology and progression. The currently available treatments are not recognized as curable options and, at best, might slow the progression of MS injuries to the CNS. However, stem cell treatment has provided a new avenue for treating MS. Stem cells may enhance CNS healing and regulate immunological responses. Likewise, stem cells can come from various sources, including adipose, neuronal, bone marrow, and embryonic tissues. Choosing the optimal cell source for stem cell therapy is still a difficult verdict. A type of stem cell known as mesenchymal stem cells (MSCs) is obtainable from different sources and has a strong immunomodulatory impact on the immune system. According to mounting data, the umbilical cord and adipose tissue may serve as appropriate sources for the isolation of MSCs. Human amniotic epithelial cells (hAECs), as novel stem cell sources with immune-regulatory effects, regenerative properties, and decreased antigenicity, can also be thought of as a new upcoming contender for MS treatment. Overall, the administration of stem cells in different sets of animal and clinical trials has shown immunomodulatory and neuroprotective results. Therefore, this review aims to discuss the different types of stem cells by focusing on MSCs and their mechanisms, which can be used to treat and improve the outcomes of MS disease.
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Affiliation(s)
| | - Amirmasoud Rayati Damavandi
- Students' Scientific Research Center, Exceptional Talents Development Center, Tehran University of Medical Sciences, Keshavarz Blvrd, Vesal Shirazi St., Tehran 1417613151, Iran
| | - Samira Moradi
- School of Medicine, Hormozgan University of Medical Sciences Chamran Blvrd., Hormozgan 7919693116, Bandar Abbass, Iran
| | - Meysam Ahmadi
- School of Medicine, Shiraz University of Medical Sciences, Fars, Zand St., Shiraz 7134814336, Iran
| | - Peyman Bemani
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Hezar Jerib St., Isfahan 8174673461, Iran
| | - Hamid Aria
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Hezar Jerib St., Isfahan 8174673461, Iran
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fars, Ibn Sina Sq., Fasa 7461686688, Iran
| | - Hossein Mottedayyen
- Department of Immunology, School of Medicine, Kashan University of Medical Sciences, Ravandi Blvrd, Isfahan, Kashan 8715988141, Iran
| | - Amirhossein Rayati Damavandi
- Student's Research Committee, Pharmaceutical Sciences Branch, Islamic Azad University, Yakhchal St., Tehran 193951498, Iran
| | - Nahid Eskandari
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Hezar Jerib St., Isfahan 8174673461, Iran
| | - Farshid Fathi
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Hezar Jerib St., Isfahan 8174673461, Iran
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17
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Ni H, Xi J, Tang J, Yan Y, Chu Y, Zhou J. Therapeutic Potential of Extracellular Vesicles from Different Stem Cells in Chronic Wound Healing. Stem Cell Rev Rep 2023; 19:1596-1614. [PMID: 37178227 DOI: 10.1007/s12015-023-10540-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/31/2023] [Indexed: 05/15/2023]
Abstract
Wound healing has long been a complex problem, especially in chronic wounds. Although debridement, skin grafting, and antimicrobial dressings have been used to treat chronic wounds, their treatment period is long, expensive, and has specific rejection reactions. The poor treatment results of traditional methods have caused psychological stress to patients and a substantial economic burden to society. Extracellular vesicles (EVs) are nanoscale vesicles secreted by cells. They play an essential role in intercellular communication. Numerous studies have confirmed that stem cell-derived extracellular vesicles (SC-EVs) can inhibit overactive inflammation, induce angiogenesis, promote re-epithelization, and reduce scar formation. Therefore, SC-EVs are expected to be a novel cell-free strategy for chronic wound treatment. We first summarize the pathological factors that hinder wound healing and discuss how SC-EVs accelerate chronic wound repair. And then, we also compare the advantages and disadvantages of different SC-EVs for chronic wound treatment. Finally, we discuss the limitations of SC-EVs usage and provide new thoughts for future SC-EVs research in chronic wound treatment.
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Affiliation(s)
- Haoxi Ni
- School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Jianbo Xi
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Changzhou, 213017, China
| | - Jianjun Tang
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Changzhou, 213017, China
- Department of General Surgery, Wujin Clinical College of Xuzhou Medical University, Changzhou, 213017, China
| | - Yongmin Yan
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Changzhou, 213017, China
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213017, China
| | - Ying Chu
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China.
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Changzhou, 213017, China.
| | - Jing Zhou
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China.
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Changzhou, 213017, China.
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18
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Bogomiakova ME, Sekretova EK, Anufrieva KS, Khabarova PO, Kazakova AN, Bobrovsky PA, Grigoryeva TV, Eremeev AV, Lebedeva OS, Bogomazova AN, Lagarkova MA. iPSC-derived cells lack immune tolerance to autologous NK-cells due to imbalance in ligands for activating and inhibitory NK-cell receptors. Stem Cell Res Ther 2023; 14:77. [PMID: 37038186 PMCID: PMC10088155 DOI: 10.1186/s13287-023-03308-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 03/28/2023] [Indexed: 04/12/2023] Open
Abstract
BACKGROUND Dozens of transplants generated from pluripotent stem cells are currently in clinical trials. The creation of patient-specific iPSCs makes personalized therapy possible due to their main advantage of immunotolerance. However, some reports have claimed recently that aberrant gene expression followed by proteome alterations and neoantigen formation can result in iPSCs recognition by autologous T-cells. Meanwhile, the possibility of NK-cell activation has not been previously considered. This study focused on the comparison of autologous and allogeneic immune response to iPSC-derived cells and isogeneic parental somatic cells used for reprogramming. METHODS We established an isogeneic cell model consisting of parental dermal fibroblasts, fibroblast-like iPSC-derivatives (iPS-fibro) and iPS-fibro lacking beta-2-microglobulin (B2M). Using the cells obtained from two patients, we analyzed the activation of autologous and allogeneic T-lymphocytes and NK-cells co-cultured with target cells. RESULTS Here we report that cells differentiated from iPSCs can be recognized by NK-cells rather than by autologous T-cells. We observed that iPS-fibro elicited a high level of NK-cell degranulation and cytotoxicity, while isogeneic parental skin fibroblasts used to obtain iPSCs barely triggered an NK-cell response. iPSC-derivatives with B2M knockout did not cause an additional increase in NK-cell activation, although they were devoid of HLA-I, the major inhibitory molecules for NK-cells. Transcriptome analysis revealed a significant imbalance of ligands for activating and inhibitory NK-cell receptors in iPS-fibro. Compared to parental fibroblasts, iPSC-derivatives had a reduced expression of HLA-I simultaneously with an increased gene expression of major activating ligands, such as MICA, NECTIN2, and PVR. The lack of inhibitory signals might be due to insufficient maturity of cells differentiated from iPSCs. In addition, we showed that pretreatment of iPS-fibro with proinflammatory cytokine IFNγ restored the ligand imbalance, thereby reducing the degranulation and cytotoxicity of NK-cells. CONCLUSION In summary, we showed that iPSC-derived cells can be sensitive to the cytotoxic potential of autologous NK-cells regardless of HLA-I status. Thus, the balance of ligands for NK-cell receptors should be considered prior to iPSC-based cell therapies. Trial registration Not applicable.
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Affiliation(s)
- Margarita E Bogomiakova
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya, Moscow, Russia, 119435.
- Faculty of Biology, Lomonosov Moscow State University, 1-12 Leninskie Gory, Moscow, Russia, 119991.
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya, Moscow, Russia, 119435.
| | - Elizaveta K Sekretova
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya, Moscow, Russia, 119435
- Faculty of Biology, Lomonosov Moscow State University, 1-12 Leninskie Gory, Moscow, Russia, 119991
| | - Ksenia S Anufrieva
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya, Moscow, Russia, 119435
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya, Moscow, Russia, 119435
| | - Polina O Khabarova
- Faculty of Biology, Lomonosov Moscow State University, 1-12 Leninskie Gory, Moscow, Russia, 119991
| | - Anastasia N Kazakova
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya, Moscow, Russia, 119435
| | - Pavel A Bobrovsky
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya, Moscow, Russia, 119435
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya, Moscow, Russia, 119435
| | | | - Artem V Eremeev
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya, Moscow, Russia, 119435
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya, Moscow, Russia, 119435
| | - Olga S Lebedeva
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya, Moscow, Russia, 119435
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya, Moscow, Russia, 119435
| | - Alexandra N Bogomazova
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya, Moscow, Russia, 119435
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya, Moscow, Russia, 119435
| | - Maria A Lagarkova
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya, Moscow, Russia, 119435
- Faculty of Biology, Lomonosov Moscow State University, 1-12 Leninskie Gory, Moscow, Russia, 119991
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Aldoghachi AF, Loh JK, Wang ML, Yang YP, Chien CS, Teh HX, Omar AH, Cheong SK, Yeap SK, Ho WY, Ong AHK. Current developments and therapeutic potentials of exosomes from induced pluripotent stem cells-derived mesenchymal stem cells. J Chin Med Assoc 2023; 86:356-365. [PMID: 36762931 DOI: 10.1097/jcma.0000000000000899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/11/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells derived from adult human tissues that have the ability to proliferate in vitro and maintain their multipotency, making them attractive cell sources for regenerative medicine. However, MSCs reportedly show limited proliferative capacity with inconsistent therapeutic outcomes due to their heterogeneous nature. On the other hand, induced pluripotent stem cells (iPSC) have emerged as an alternative source for the production of various specialized cell types via their ability to differentiate from all three primary germ layers, leading to applications in regenerative medicine, disease modeling, and drug therapy. Notably, iPSCs can differentiate into MSCs in monolayer, commonly referred to as induced mesenchymal stem cells (iMSCs). These cells show superior therapeutic qualities compared with adult MSCs as the applications of the latter are restricted by passage number and autoimmune rejection when applied in tissue regeneration trials. Furthermore, increasing evidence shows that the therapeutic properties of stem cells are a consequence of the paracrine effects mediated by their secretome such as from exosomes, a type of extracellular vesicle secreted by most cell types. Several studies that investigated the potential of exosomes in regenerative medicine and therapy have revealed promising results. Therefore, this review focuses on the recent findings of exosomes secreted from iMSCs as a potential noncell-based therapy.
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Affiliation(s)
- Ahmed Faris Aldoghachi
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Jit-Kai Loh
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Mong-Lien Wang
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Ping Yang
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chian-Shiu Chien
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Hui Xin Teh
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Alfaqih Hussain Omar
- Biomedicine Programme, School of Health Sciences, Universiti Sains Malaysia, Malaysia
| | - Soon-Keng Cheong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
- National Cancer Council (MAKNA), Kuala Lumpur, Malaysia
| | - Swee Keong Yeap
- Marine Biotechnology, China-ASEAN College of Marine Sciences, Xiamen University Malaysia Campus, Jalan Sunsuria, Bandar Sunsuria, Sepang, Selangor, Malaysia
| | - Wan Yong Ho
- Faculty of Sciences and Engineering, University of Nottingham Malaysia, Semenyih, Malaysia
| | - Alan Han-Kiat Ong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
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20
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Ichimura H, Chino S, Shiba Y. Cardiac Regeneration Using Pluripotent Stem Cells and Controlling Immune Responses. Heart Lung Circ 2023:S1443-9506(23)00108-7. [PMID: 37029069 DOI: 10.1016/j.hlc.2022.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 11/02/2022] [Accepted: 12/05/2022] [Indexed: 04/08/2023]
Abstract
Pluripotent stem cell (PSC)-derived cardiomyocytes are a promising source of cells in myocardial regeneration therapy for end-stage heart failure. Because most previous reports have focussed on xenotransplantation models using immunocompromised animals, studies on immune rejection in allogeneic transplantation models are needed for preclinical and clinical applications. Human leukocyte antigen (HLA) plays an important role in allogeneic transplantation, and cell bank projects are currently underway worldwide to stock induced pluripotent stem cells (iPSCs) generated from healthy individuals with homozygous HLA haplotypes. However, it is difficult to stock iPSCs that match the entire population in these cell banks; thus, several groups have produced hypoimmunogenic PSCs by knocking out HLA. These HLA-knockout PSCs were able to avoid rejection by T cells but still suffered rejection by natural killer (NK) cells caused by 'missing self-recognition'. Recent studies have attempted to generate hypoimmunogenic PSCs with gene editing to inhibit NK cell activation. Regenerative medicine using autologous iPSCs can be an ideal transplantation therapy, but, currently, there are major hurdles to its practical application. Hopefully, further research will resolve these issues. This review provides an overview of the current understanding and progress in this field.
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Affiliation(s)
- Hajime Ichimura
- Department of Regenerative Science and Medicine, Shinshu University School of Medicine, Matsumoto, Japan; Department of Surgery, Division of Cardiovascular Surgery, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shuji Chino
- Department of Surgery, Division of Cardiovascular Surgery, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yuji Shiba
- Department of Regenerative Science and Medicine, Shinshu University School of Medicine, Matsumoto, Japan; Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan.
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21
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Yu Y, Tham SK, Roslan FF, Shaharuddin B, Yong YK, Guo Z, Tan JJ. Large animal models for cardiac remuscularization studies: A methodological review. Front Cardiovasc Med 2023; 10:1011880. [PMID: 37008331 PMCID: PMC10050756 DOI: 10.3389/fcvm.2023.1011880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 02/20/2023] [Indexed: 03/17/2023] Open
Abstract
Myocardial infarction is the most common cause of heart failure, one of the most fatal non-communicable diseases worldwide. The disease could potentially be treated if the dead, ischemic heart tissues are regenerated and replaced with viable and functional cardiomyocytes. Pluripotent stem cells have proven the ability to derive specific and functional cardiomyocytes in large quantities for therapy. To test the remuscularization hypothesis, the strategy to model the disease in animals must resemble the pathophysiological conditions of myocardial infarction as in humans, to enable thorough testing of the safety and efficacy of the cardiomyocyte therapy before embarking on human trials. Rigorous experiments and in vivo findings using large mammals are increasingly important to simulate clinical reality and increase translatability into clinical practice. Hence, this review focus on large animal models which have been used in cardiac remuscularization studies using cardiomyocytes derived from human pluripotent stem cells. The commonly used methodologies in developing the myocardial infarction model, the choice of animal species, the pre-operative antiarrhythmics prophylaxis, the choice of perioperative sedative, anaesthesia and analgesia, the immunosuppressive strategies in allowing xenotransplantation, the source of cells, number and delivery method are discussed.
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Affiliation(s)
- Yuexin Yu
- USM-ALPS Cardiac Research Laboratory, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang, Malaysia
- Henan Key Laboratory of Cardiac Remodeling and Transplantation, Zhengzhou Seventh People's Hospital, China
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, China
| | | | - Fatin Fazrina Roslan
- USM-ALPS Cardiac Research Laboratory, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang, Malaysia
| | - Bakiah Shaharuddin
- USM-ALPS Cardiac Research Laboratory, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang, Malaysia
| | - Yoke Keong Yong
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Zhikun Guo
- Henan Key Laboratory of Cardiac Remodeling and Transplantation, Zhengzhou Seventh People's Hospital, China
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, China
- Correspondence: Jun Jie Tan Zhikun Guo
| | - Jun Jie Tan
- USM-ALPS Cardiac Research Laboratory, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang, Malaysia
- Correspondence: Jun Jie Tan Zhikun Guo
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22
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Bohrer LR, Stone NE, Mullin NK, Voigt AP, Anfinson KR, Fick JL, Luangphakdy V, Hittle B, Powell K, Muschler GF, Mullins RF, Stone EM, Tucker BA. Automating iPSC generation to enable autologous photoreceptor cell replacement therapy. J Transl Med 2023; 21:161. [PMID: 36855199 PMCID: PMC9976478 DOI: 10.1186/s12967-023-03966-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 02/03/2023] [Indexed: 03/02/2023] Open
Abstract
BACKGROUND Inherited retinal degeneration is a leading cause of incurable vision loss in the developed world. While autologous iPSC mediated photoreceptor cell replacement is theoretically possible, the lack of commercially available technologies designed to enable high throughput parallel production of patient specific therapeutics has hindered clinical translation. METHODS In this study, we describe the use of the Cell X precision robotic cell culture platform to enable parallel production of clinical grade patient specific iPSCs. The Cell X is housed within an ISO Class 5 cGMP compliant closed aseptic isolator (Biospherix XVivo X2), where all procedures from fibroblast culture to iPSC generation, clonal expansion and retinal differentiation were performed. RESULTS Patient iPSCs generated using the Cell X platform were determined to be pluripotent via score card analysis and genetically stable via karyotyping. As determined via immunostaining and confocal microscopy, iPSCs generated using the Cell X platform gave rise to retinal organoids that were indistinguishable from organoids derived from manually generated iPSCs. In addition, at 120 days post-differentiation, single-cell RNA sequencing analysis revealed that cells generated using the Cell X platform were comparable to those generated under manual conditions in a separate laboratory. CONCLUSION We have successfully developed a robotic iPSC generation platform and standard operating procedures for production of high-quality photoreceptor precursor cells that are compatible with current good manufacturing practices. This system will enable clinical grade production of iPSCs for autologous retinal cell replacement.
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Affiliation(s)
- Laura R Bohrer
- Institute for Vision Research, Carver College of Medicine, University of Iowa, 375 Newton Road, Iowa City, IA, 52242, USA
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Nicholas E Stone
- Institute for Vision Research, Carver College of Medicine, University of Iowa, 375 Newton Road, Iowa City, IA, 52242, USA
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Nathaniel K Mullin
- Institute for Vision Research, Carver College of Medicine, University of Iowa, 375 Newton Road, Iowa City, IA, 52242, USA
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Andrew P Voigt
- Institute for Vision Research, Carver College of Medicine, University of Iowa, 375 Newton Road, Iowa City, IA, 52242, USA
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Kristin R Anfinson
- Institute for Vision Research, Carver College of Medicine, University of Iowa, 375 Newton Road, Iowa City, IA, 52242, USA
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Jessica L Fick
- Institute for Vision Research, Carver College of Medicine, University of Iowa, 375 Newton Road, Iowa City, IA, 52242, USA
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Viviane Luangphakdy
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Cell X Technologies Inc, Cleveland, OH, USA
| | - Bradley Hittle
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA
| | - Kimerly Powell
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA
| | - George F Muschler
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Orthopaedic Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Robert F Mullins
- Institute for Vision Research, Carver College of Medicine, University of Iowa, 375 Newton Road, Iowa City, IA, 52242, USA
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Edwin M Stone
- Institute for Vision Research, Carver College of Medicine, University of Iowa, 375 Newton Road, Iowa City, IA, 52242, USA
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Budd A Tucker
- Institute for Vision Research, Carver College of Medicine, University of Iowa, 375 Newton Road, Iowa City, IA, 52242, USA.
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
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23
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Bio-Artificial Liver Support System: A Prospective Future Therapy. LIVERS 2023. [DOI: 10.3390/livers3010006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023] Open
Abstract
Whether acute or chronic, liver failure is a state of liver dysfunction that can progress to multiorgan failure. Mortality in liver failure patients is approximately 80–90% and is caused by detoxification failure, which triggers other immediate complications, such as encephalopathy, coagulopathy, jaundice, cholestasis, and acute kidney failure. The ideal treatment for liver failure is liver transplantation, but the long waiting period for the right donor match causes unavoidable deaths in most patients. Therefore, new therapies, such as tissue engineering, hepatocyte transplantation, and stem cells, are now being studied to anticipate the patient’s condition while waiting for liver transplantation. This literature review investigated the effectiveness of some bio-artificial liver support systems using review methods systematically from international publication sites, including PubMed, using keywords, such as bio-artificial liver, acute and chronic liver failure, extracorporeal liver support system (ECLS), MARS, single-pass albumin dialysis (SPAD). Artificial and bioartificial liver systems can show specific detoxification abilities and pathophysiological improvements in liver failure patients but cannot reach the ideal criteria for actual liver function. The liver support system must provide the metabolic and synthetic function as in the actual liver while reducing the pathophysiological changes in liver failure. Aspects of safety, cost efficiency, and practicality are also considered. Identifying the technology to produce high-quality hepatocytes on a big scale is essential as a medium to replace failing liver cells. An increase in detoxification capacity and therapeutic effectiveness must also focus on patient survival and the ability to perform liver transplantation.
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24
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Lu ZG, Shen J, Yang J, Wang JW, Zhao RC, Zhang TL, Guo J, Zhang X. Nucleic acid drug vectors for diagnosis and treatment of brain diseases. Signal Transduct Target Ther 2023; 8:39. [PMID: 36650130 PMCID: PMC9844208 DOI: 10.1038/s41392-022-01298-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 12/08/2022] [Accepted: 12/21/2022] [Indexed: 01/18/2023] Open
Abstract
Nucleic acid drugs have the advantages of rich target selection, simple in design, good and enduring effect. They have been demonstrated to have irreplaceable superiority in brain disease treatment, while vectors are a decisive factor in therapeutic efficacy. Strict physiological barriers, such as degradation and clearance in circulation, blood-brain barrier, cellular uptake, endosome/lysosome barriers, release, obstruct the delivery of nucleic acid drugs to the brain by the vectors. Nucleic acid drugs against a single target are inefficient in treating brain diseases of complex pathogenesis. Differences between individual patients lead to severe uncertainties in brain disease treatment with nucleic acid drugs. In this Review, we briefly summarize the classification of nucleic acid drugs. Next, we discuss physiological barriers during drug delivery and universal coping strategies and introduce the application methods of these universal strategies to nucleic acid drug vectors. Subsequently, we explore nucleic acid drug-based multidrug regimens for the combination treatment of brain diseases and the construction of the corresponding vectors. In the following, we address the feasibility of patient stratification and personalized therapy through diagnostic information from medical imaging and the manner of introducing contrast agents into vectors. Finally, we take a perspective on the future feasibility and remaining challenges of vector-based integrated diagnosis and gene therapy for brain diseases.
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Affiliation(s)
- Zhi-Guo Lu
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China.
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China.
| | - Jie Shen
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Jun Yang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Jing-Wen Wang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China
| | - Rui-Chen Zhao
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Tian-Lu Zhang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China
| | - Jing Guo
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China
| | - Xin Zhang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China.
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China.
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25
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Roman G, Stavik B, Lauritzen KH, Sandset PM, Harrison SP, Sullivan GJ, Chollet ME. "iPSC-derived liver organoids and inherited bleeding disorders: Potential and future perspectives". Front Physiol 2023; 14:1094249. [PMID: 36711019 PMCID: PMC9880334 DOI: 10.3389/fphys.2023.1094249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 01/02/2023] [Indexed: 01/15/2023] Open
Abstract
The bleeding phenotype of hereditary coagulation disorders is caused by the low or undetectable activity of the proteins involved in hemostasis, due to a broad spectrum of genetic alterations. Most of the affected coagulation factors are produced in the liver. Therefore, two-dimensional (2D) cultures of primary human hepatocytes and recombinant overexpression of the factors in non-human cell lines have been primarily used to mimic disease pathogenesis and as a model for innovative therapeutic strategies. However, neither human nor animal cells fully represent the hepatocellular biology and do not harbor the exact genetic background of the patient. As a result, the inability of the current in vitro models in recapitulating the in vivo situation has limited the studies of these inherited coagulation disorders. Induced Pluripotent Stem Cell (iPSC) technology offers a possible solution to overcome these limitations by reprogramming patient somatic cells into an embryonic-like pluripotent state, thus giving the possibility of generating an unlimited number of liver cells needed for modeling or therapeutic purposes. By combining this potential and the recent advances in the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 technology, it allows for the generation of autologous and gene corrected liver cells in the form of three-dimensional (3D) liver organoids. The organoids recapitulate cellular composition and organization of the liver, providing a more physiological model to study the biology of coagulation proteins and modeling hereditary coagulation disorders. This advanced methodology can pave the way for the development of cell-based therapeutic approaches to treat inherited coagulation disorders. In this review we will explore the use of liver organoids as a state-of-the-art methodology for modeling coagulation factors disorders and the possibilities of using organoid technology to treat the disease.
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Affiliation(s)
- Giacomo Roman
- Department of Hematology, Oslo University Hospital, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Benedicte Stavik
- Department of Hematology, Oslo University Hospital, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
| | - Knut H. Lauritzen
- Department of Hematology, Oslo University Hospital, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Per Morten Sandset
- Department of Hematology, Oslo University Hospital, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Sean P. Harrison
- Department of Pediatric Research, Oslo University Hospital, Oslo, Norway
| | - Gareth J. Sullivan
- Department of Pediatric Research, Oslo University Hospital, Oslo, Norway
- Department of Immunology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Maria Eugenia Chollet
- Department of Hematology, Oslo University Hospital, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
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26
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Naqvi RA, Naqvi AR, Singh A, Priyadarshini M, Balamurugan AN, Layden BT. The future treatment for type 1 diabetes: Pig islet- or stem cell-derived β cells? Front Endocrinol (Lausanne) 2023; 13:1001041. [PMID: 36686451 PMCID: PMC9849241 DOI: 10.3389/fendo.2022.1001041] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 12/07/2022] [Indexed: 01/06/2023] Open
Abstract
Replacement of β cells is only a curative approach for type 1 diabetes (T1D) patients to avoid the threat of iatrogenic hypoglycemia. In this pursuit, islet allotransplantation under Edmonton's protocol emerged as a medical miracle to attain hypoglycemia-free insulin independence in T1D. Shortage of allo-islet donors and post-transplantation (post-tx) islet loss are still unmet hurdles for the widespread application of this therapeutic regimen. The long-term survival and effective insulin independence in preclinical studies have strongly suggested pig islets to cure overt hyperglycemia. Importantly, CRISPR-Cas9 technology is pursuing to develop "humanized" pig islets that could overcome the lifelong immunosuppression drug regimen. Lately, induced pluripotent stem cell (iPSC)-derived β cell approaches are also gaining momentum and may hold promise to yield a significant supply of insulin-producing cells. Theoretically, personalized β cells derived from a patient's iPSCs is one exciting approach, but β cell-specific immunity in T1D recipients would still be a challenge. In this context, encapsulation studies on both pig islet as well as iPSC-β cells were found promising and rendered long-term survival in mice. Oxygen tension and blood vessel growth within the capsules are a few of the hurdles that need to be addressed. In conclusion, challenges associated with both procedures, xenotransplantation (of pig-derived islets) and stem cell transplantation, are required to be cautiously resolved before their clinical application.
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Affiliation(s)
- Raza Ali Naqvi
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL, United States
| | - Afsar Raza Naqvi
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL, United States
| | - Amar Singh
- Department of Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Medha Priyadarshini
- Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Appakalai N. Balamurugan
- Center for Clinical and Translational Research, Nationwide Children’s Hospital, Columbus, OH, United States
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, United States
| | - Brian T. Layden
- Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
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27
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Behl T, Kaur I, Sehgal A, Singh S, Sharma N, Chigurupati S, Felemban SG, Alsubayiel AM, Iqbal MS, Bhatia S, Al-Harrasi A, Bungau S, Mostafavi E. "Cutting the Mustard" with Induced Pluripotent Stem Cells: An Overview and Applications in Healthcare Paradigm. Stem Cell Rev Rep 2022; 18:2757-2780. [PMID: 35793037 DOI: 10.1007/s12015-022-10390-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/15/2022] [Indexed: 12/09/2022]
Abstract
Treatment of numerous ailments has been made accessible by the advent of genetic engineering, where the self-renewal property has unfolded the mysteries of regeneration, i.e., stem cells. This is narrowed down to pluripotency, the cell property of differentiating into other adult cells. The generation of induced pluripotent stem cells (iPSCs) was a major breakthrough in 2006, which was generated by a cocktail of 4 Yamanaka Factors, following which significant advancements have been reported in medical science and therapeutics. The iPSCs are reprogrammed from somatic cells, and the fascinating results focused on developing authentic techniques for their generation via molecular reprogramming mechanisms, with a plethora of molecules, like NANOG, miRNAs, and DNA modifying agents, etc. The iPSCs have exhibited reliable results in assessing the etiology and molecular mechanisms of diseases, followed by the development of possible treatments and the elimination of risks of immune rejection. The authors formulate a comprehensive review to develop a clear understanding of iPSC generation, their advantages and limitations, with potential challenges associated with their medical utility. In addition, a wide compendium of applications of iPSCs in regenerative medicine and disease modeling has been discussed, alongside bioengineering technologies for iPSC reprogramming, expansion, isolation, and differentiation. The manuscript aims to provide a holistic picture of the booming advancement of iPSC therapy, to attract the attention of global researchers, to investigate this versatile approach in treatment of multiple disorders, subsequently overcoming the challenges, in order to effectively expand its therapeutic window.
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Affiliation(s)
- Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India.
| | - Ishnoor Kaur
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Sridevi Chigurupati
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraydah, Kingdom of Saudi Arabia
| | - Shatha Ghazi Felemban
- Department of Medical Laboratory Science, Fakeeh College for Medical Sciences, Jeddah, Kingdom of Saudi Arabia
| | - Amal M Alsubayiel
- Department of Pharmaceutics, College of Pharmacy, Qassim University, Buraydah, Kingdom of Saudi Arabia
| | - Muhammad Shahid Iqbal
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam bin Abdulaziz University, Alkharj, Saudi Arabia
| | - Saurabh Bhatia
- Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
- School of Health Science, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
| | - Ebrahim Mostafavi
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
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Thanaskody K, Jusop AS, Tye GJ, Wan Kamarul Zaman WS, Dass SA, Nordin F. MSCs vs. iPSCs: Potential in therapeutic applications. Front Cell Dev Biol 2022; 10:1005926. [PMID: 36407112 PMCID: PMC9666898 DOI: 10.3389/fcell.2022.1005926] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/21/2022] [Indexed: 01/24/2023] Open
Abstract
Over the past 2 decades, mesenchymal stem cells (MSCs) have attracted a lot of interest as a unique therapeutic approach for a variety of diseases. MSCs are capable of self-renewal and multilineage differentiation capacity, immunomodulatory, and anti-inflammatory properties allowing it to play a role in regenerative medicine. Furthermore, MSCs are low in tumorigenicity and immune privileged, which permits the use of allogeneic MSCs for therapies that eliminate the need to collect MSCs directly from patients. Induced pluripotent stem cells (iPSCs) can be generated from adult cells through gene reprogramming with ectopic expression of specific pluripotency factors. Advancement in iPS technology avoids the destruction of embryos to make pluripotent cells, making it free of ethical concerns. iPSCs can self-renew and develop into a plethora of specialized cells making it a useful resource for regenerative medicine as they may be created from any human source. MSCs have also been used to treat individuals infected with the SARS-CoV-2 virus. MSCs have undergone more clinical trials than iPSCs due to high tumorigenicity, which can trigger oncogenic transformation. In this review, we discussed the overview of mesenchymal stem cells and induced pluripotent stem cells. We briefly present therapeutic approaches and COVID-19-related diseases using MSCs and iPSCs.
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Affiliation(s)
- Kalaiselvaan Thanaskody
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Amirah Syamimi Jusop
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Gee Jun Tye
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Gelugor, Malaysia
| | - Wan Safwani Wan Kamarul Zaman
- Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Kuala Lumpur, Malaysia,Centre for Innovation in Medical Engineering (CIME), Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Sylvia Annabel Dass
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Gelugor, Malaysia
| | - Fazlina Nordin
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia,*Correspondence: Fazlina Nordin,
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Lyadova I, Vasiliev A. Macrophages derived from pluripotent stem cells: prospective applications and research gaps. Cell Biosci 2022; 12:96. [PMID: 35725499 PMCID: PMC9207879 DOI: 10.1186/s13578-022-00824-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 05/29/2022] [Indexed: 11/10/2022] Open
Abstract
Induced pluripotent stem cells (iPSCs) represent a valuable cell source able to give rise to different cell types of the body. Among the various pathways of iPSC differentiation, the differentiation into macrophages is a recently developed and rapidly growing technique. Macrophages play a key role in the control of host homeostasis. Their dysfunction underlies many diseases, including hereditary, infectious, oncological, metabolic and other disorders. Targeting macrophage activity and developing macrophage-based cell therapy represent promising tools for the treatment of many pathological conditions. Macrophages generated from human iPSCs (iMphs) provide great opportunities in these areas. The generation of iMphs is based on a step-wise differentiation of iPSCs into mesoderm, hematopoietic progenitors, myeloid monocyte-like cells and macrophages. The technique allows to obtain standardizable populations of human macrophages from any individual, scale up macrophage production and introduce genetic modifications, which gives significant advantages over the standard source of human macrophages, monocyte-derived macrophages. The spectrum of iMph applications is rapidly growing. iMphs have been successfully used to model hereditary diseases and macrophage-pathogen interactions, as well as to test drugs. iMph use for cell therapy is another promising and rapidly developing area of research. The principles and the details of iMph generation have recently been reviewed. This review systemizes current and prospective iMph applications and discusses the problem of iMph safety and other issues that need to be explored before iMphs become clinically applicable.
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Affiliation(s)
- Irina Lyadova
- Koltzov Institute of Developmental Biology of RAS, Moscow, Russian Federation.
| | - Andrei Vasiliev
- Koltzov Institute of Developmental Biology of RAS, Moscow, Russian Federation
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Utility of iPSC-Derived Cells for Disease Modeling, Drug Development, and Cell Therapy. Cells 2022; 11:cells11111853. [PMID: 35681550 PMCID: PMC9180434 DOI: 10.3390/cells11111853] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 05/28/2022] [Accepted: 06/02/2022] [Indexed: 02/04/2023] Open
Abstract
The advent of induced pluripotent stem cells (iPSCs) has advanced our understanding of the molecular mechanisms of human disease, drug discovery, and regenerative medicine. As such, the use of iPSCs in drug development and validation has shown a sharp increase in the past 15 years. Furthermore, many labs have been successful in reproducing many disease phenotypes, often difficult or impossible to capture, in commonly used cell lines or animal models. However, there still remain limitations such as the variability between iPSC lines as well as their maturity. Here, we aim to discuss the strategies in generating iPSC-derived cardiomyocytes and neurons for use in disease modeling, drug development and their use in cell therapy.
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Liang D, Sun Q, Zhu Z, Wang C, Ye S, Li Z, Wang Y. Xenotransplantation of Human Spermatogonia Into Various Mouse Recipient Models. Front Cell Dev Biol 2022; 10:883314. [PMID: 35676935 PMCID: PMC9168328 DOI: 10.3389/fcell.2022.883314] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 04/20/2022] [Indexed: 12/28/2022] Open
Abstract
Spermatogonial stem cells are the foundation of continuous spermatogenesis in adult mammals. Xenograft models have been established to define human SSCs, mostly using infertile and immune-deficient mice as the recipients for human germ cell transplantation. However, it is time-consuming to prepare such recipients using irradiation or chemotherapeutic agents, and this approach may also introduce confounding factors when residual endogenous germ cells recover in transplanted recipients. It remains to be determined whether immune-competent genetically infertile mice can be suitable recipients for xenotransplantation. In this study, we observed similar engraftment efficiencies when using spermatogonia from human biopsied testes across immune-deficient nude mice, immune-competent ICR mice, and genetically infertile Kit w/w-v mice, suggesting minimal immunological rejection from immune-competent mouse recipients upon xenotransplantation of human germ cells. More importantly, we derived EpCAM negative and TNAP positive spermatogonia-like cells (SLCs) from human pluripotent stem cells (PSCs), which highly expressed spermatogonial markers including PLZF, INTERGRINα6, TKTL1, CD90, and DRMT3. We found that upon transplantation, these SLCs proliferated and colonized at the basal membrane of seminiferous tubules in testes of both immune-deficient nude mice and Kit w/w-v mice, though complete spermatogenesis would likely require supporting human signaling factors and microenvironment. Taken together, our study functionally defined the cell identity of PSC-derived SLCs, and supported xenotransplantation using genetically infertile recipients as a convenient model for functionally evaluating spermatogonia derived from different species.
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Affiliation(s)
- Dongli Liang
- Laboratory Animal Center, Instrumental Analysis Center, Shanghai Jiao Tong University, Shanghai, China
| | - Qi Sun
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Zijue Zhu
- Department of Andrology, The Center for Men’s Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chuanyun Wang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Shicheng Ye
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Zheng Li
- Department of Andrology, The Center for Men’s Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuan Wang
- Department of Animal Sciences, College of Agriculture and Natural Resources, Michigan State University, East Lansing, MI, United States
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Rossbach B, Hariharan K, Mah N, Oh SJ, Volk HD, Reinke P, Kurtz A. Human iPSC-Derived Renal Cells Change Their Immunogenic Properties during Maturation: Implications for Regenerative Therapies. Cells 2022; 11:cells11081328. [PMID: 35456007 PMCID: PMC9032821 DOI: 10.3390/cells11081328] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 12/24/2022] Open
Abstract
The success of human induced pluripotent stem cell (hiPSC)-based therapy critically depends on understanding and controlling the immunological effects of the hiPSC-derived transplant. While hiPSC-derived cells used for cell therapy are often immature with post-grafting maturation, immunological properties may change, with adverse effects on graft tolerance and control. In the present study, the allogeneic and autologous cellular immunity of hiPSC-derived progenitor and terminally differentiated cells were investigated in vitro. In contrast to allogeneic primary cells, hiPSC-derived early renal progenitors and mature renal epithelial cells are both tolerated not only by autologous but also by allogeneic T cells. These immune-privileged properties result from active immunomodulation and low immune visibility, which decrease during the process of cell maturation. However, autologous and allogeneic natural killer (NK) cell responses are not suppressed by hiPSC-derived renal cells and effectively change NK cell activation status. These findings clearly show a dynamic stage-specific dependency of autologous and allogeneic T and NK cell responses, with consequences for effective cell therapies. The study suggests that hiPSC-derived early progenitors may provide advantageous immune-suppressive properties when applied in cell therapy. The data furthermore indicate a need to suppress NK cell activation in allogeneic as well as autologous settings.
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Affiliation(s)
- Bella Rossbach
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; (K.H.); (S.-J.O.); (H.-D.V.); (P.R.)
- Fraunhofer Institute for Biomedical Engineering (IBMT), Fraunhofer-Forum Berlin, 10178 Berlin, Germany;
- Correspondence: (B.R.); (A.K.)
| | - Krithika Hariharan
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; (K.H.); (S.-J.O.); (H.-D.V.); (P.R.)
- Fraunhofer Institute for Biomedical Engineering (IBMT), Fraunhofer Project Center for Stem Cell Processing, 97082 Würzburg, Germany
| | - Nancy Mah
- Fraunhofer Institute for Biomedical Engineering (IBMT), Fraunhofer-Forum Berlin, 10178 Berlin, Germany;
| | - Su-Jun Oh
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; (K.H.); (S.-J.O.); (H.-D.V.); (P.R.)
| | - Hans-Dieter Volk
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; (K.H.); (S.-J.O.); (H.-D.V.); (P.R.)
- Institute for Medical Immunology (IMI), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Petra Reinke
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; (K.H.); (S.-J.O.); (H.-D.V.); (P.R.)
- Berlin Center for Advanced Therapies (BeCat), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Andreas Kurtz
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; (K.H.); (S.-J.O.); (H.-D.V.); (P.R.)
- Fraunhofer Institute for Biomedical Engineering (IBMT), Fraunhofer-Forum Berlin, 10178 Berlin, Germany;
- Correspondence: (B.R.); (A.K.)
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Shukla AK, Gao G, Kim BS. Applications of 3D Bioprinting Technology in Induced Pluripotent Stem Cells-Based Tissue Engineering. MICROMACHINES 2022; 13:155. [PMID: 35208280 PMCID: PMC8876961 DOI: 10.3390/mi13020155] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/17/2022] [Accepted: 01/18/2022] [Indexed: 02/01/2023]
Abstract
Induced pluripotent stem cells (iPSCs) are essentially produced by the genetic reprogramming of adult cells. Moreover, iPSC technology prevents the genetic manipulation of embryos. Hence, with the ensured element of safety, they rarely cause ethical concerns when utilized in tissue engineering. Several cumulative outcomes have demonstrated the functional superiority and potency of iPSCs in advanced regenerative medicine. Recently, an emerging trend in 3D bioprinting technology has been a more comprehensive approach to iPSC-based tissue engineering. The principal aim of this review is to provide an understanding of the applications of 3D bioprinting in iPSC-based tissue engineering. This review discusses the generation of iPSCs based on their distinct purpose, divided into two categories: (1) undifferentiated iPSCs applied with 3D bioprinting; (2) differentiated iPSCs applied with 3D bioprinting. Their significant potential is analyzed. Lastly, various applications for engineering tissues and organs have been introduced and discussed in detail.
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Affiliation(s)
- Arvind Kumar Shukla
- School of Biomedical Convergence Engineering, Pusan National University, Yangsan 50612, Korea;
| | - Ge Gao
- Institute of Engineering Medicine, Beijing Institute of Technology, Beijing 100081, China
- Department of Medical Technology, Beijing Institute of Technology, Beijing 100081, China
| | - Byoung Soo Kim
- School of Biomedical Convergence Engineering, Pusan National University, Yangsan 50612, Korea;
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Pluripotent Stem Cell-Derived Hepatocytes Inhibit T Cell Proliferation In Vitro through Tryptophan Starvation. Cells 2021; 11:cells11010024. [PMID: 35011586 PMCID: PMC8750013 DOI: 10.3390/cells11010024] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/14/2021] [Accepted: 12/17/2021] [Indexed: 11/17/2022] Open
Abstract
Regenerative medicine aims to replace damaged tissues by stimulating endogenous tissue repair or by transplanting autologous or allogeneic cells. Due to their capacity to produce unlimited numbers of cells of a given cell type, pluripotent stem cells, whether of embryonic origin or induced via the reprogramming of somatic cells, are of considerable therapeutic interest in the regenerative medicine field. However, regardless of the cell type, host immune responses present a barrier to success. The aim of this study was to investigate in vitro the immunological properties of human pluripotent stem cell (PSC)-derived hepatocyte-like cells (HLCs). These cells expressed MHC class I molecules while they lacked MHC class II and co-stimulatory molecules, such as CD80 and CD86. Following stimulation with IFN-γ, HLCs upregulated CD40, PD-L1 and MHC class I molecules. When co-cultured with allogeneic T cells, HLCs did not induce T cell proliferation; furthermore, when T cells were stimulated via αCD3/CD28 beads, HLCs inhibited their proliferation via IDO1 and tryptophan deprivation. These results demonstrate that PSC-derived HLCs possess immunoregulatory functions, at least in vitro.
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35
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Zhang L, Sun H, Zhao J, Lee J, Ee Low L, Gong L, Chen Y, Wang N, Zhu C, Lin P, Liang Z, Wei M, Ling D, Li F. Dynamic nanoassemblies for imaging and therapy of neurological disorders. Adv Drug Deliv Rev 2021; 175:113832. [PMID: 34146626 DOI: 10.1016/j.addr.2021.113832] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/07/2021] [Accepted: 06/11/2021] [Indexed: 02/07/2023]
Abstract
The past decades have witnessed an increased incidence of neurological disorders (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, ischemic stroke, and epilepsy, which significantly lower patients' life quality and increase the economic and social burden. Recently, nanomedicines composed of imaging and/or therapeutic agents have been explored to diagnose and/or treat NDs due to their enhanced bioavailability, blood-brain barrier (BBB) permeability, and targeting capacity. Intriguingly, dynamic nanoassemblies self-assembled from functional nanoparticles to simultaneously interfere with multiple pathogenic substances and pathological changes, have been regarded as one of the foremost candidates to improve the diagnostic and therapeutic efficacy of NDs. To help readers better understand this emerging field, in this review, the pathogenic mechanism of different types of NDs is briefly introduced, then the functional nanoparticles used as building blocks in the construction of dynamic nanoassemblies for NDs theranostics are summarized. Furthermore, dynamic nanoassemblies that can actively cross the BBB to target brain lesions, sensitively and efficiently diagnose or treat NDs, and effectively promote neuroregeneration are highlighted. Finally, we conclude with our perspectives on the future development in this field.
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36
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Gähwiler EKN, Motta SE, Martin M, Nugraha B, Hoerstrup SP, Emmert MY. Human iPSCs and Genome Editing Technologies for Precision Cardiovascular Tissue Engineering. Front Cell Dev Biol 2021; 9:639699. [PMID: 34262897 PMCID: PMC8273765 DOI: 10.3389/fcell.2021.639699] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 03/31/2021] [Indexed: 12/12/2022] Open
Abstract
Induced pluripotent stem cells (iPSCs) originate from the reprogramming of adult somatic cells using four Yamanaka transcription factors. Since their discovery, the stem cell (SC) field achieved significant milestones and opened several gateways in the area of disease modeling, drug discovery, and regenerative medicine. In parallel, the emergence of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR-Cas9) revolutionized the field of genome engineering, allowing the generation of genetically modified cell lines and achieving a precise genome recombination or random insertions/deletions, usefully translated for wider applications. Cardiovascular diseases represent a constantly increasing societal concern, with limited understanding of the underlying cellular and molecular mechanisms. The ability of iPSCs to differentiate into multiple cell types combined with CRISPR-Cas9 technology could enable the systematic investigation of pathophysiological mechanisms or drug screening for potential therapeutics. Furthermore, these technologies can provide a cellular platform for cardiovascular tissue engineering (TE) approaches by modulating the expression or inhibition of targeted proteins, thereby creating the possibility to engineer new cell lines and/or fine-tune biomimetic scaffolds. This review will focus on the application of iPSCs, CRISPR-Cas9, and a combination thereof to the field of cardiovascular TE. In particular, the clinical translatability of such technologies will be discussed ranging from disease modeling to drug screening and TE applications.
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Affiliation(s)
- Eric K. N. Gähwiler
- Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland
| | - Sarah E. Motta
- Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland
- Wyss Zurich, University and ETH Zurich, Zurich, Switzerland
| | - Marcy Martin
- Division of Pediatric Cardiology, Department of Pediatrics, Stanford School of Medicine, Stanford, CA, United States
- Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford School of Medicine, Stanford, CA, United States
- Stanford Cardiovascular Institute, Stanford School of Medicine, Stanford, CA, United States
| | - Bramasta Nugraha
- Molecular Parasitology Lab, Institute of Parasitology, University of Zurich, Zurich, Switzerland
- Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism, R&D BioPharmaceuticals, AstraZeneca, Gothenburg, Sweden
| | - Simon P. Hoerstrup
- Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland
- Wyss Zurich, University and ETH Zurich, Zurich, Switzerland
| | - Maximilian Y. Emmert
- Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland
- Wyss Zurich, University and ETH Zurich, Zurich, Switzerland
- Department of Cardiovascular Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany
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Petrus-Reurer S, Romano M, Howlett S, Jones JL, Lombardi G, Saeb-Parsy K. Immunological considerations and challenges for regenerative cellular therapies. Commun Biol 2021; 4:798. [PMID: 34172826 PMCID: PMC8233383 DOI: 10.1038/s42003-021-02237-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 05/17/2021] [Indexed: 02/06/2023] Open
Abstract
The central goal of regenerative medicine is to replace damaged or diseased tissue with cells that integrate and function optimally. The capacity of pluripotent stem cells to produce unlimited numbers of differentiated cells is of considerable therapeutic interest, with several clinical trials underway. However, the host immune response represents an important barrier to clinical translation. Here we describe the role of the host innate and adaptive immune responses as triggers of allogeneic graft rejection. We discuss how the immune response is determined by the cellular therapy. Additionally, we describe the range of available in vitro and in vivo experimental approaches to examine the immunogenicity of cellular therapies, and finally we review potential strategies to ameliorate immune rejection. In conclusion, we advocate establishment of platforms that bring together the multidisciplinary expertise and infrastructure necessary to comprehensively investigate the immunogenicity of cellular therapies to ensure their clinical safety and efficacy.
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Affiliation(s)
- Sandra Petrus-Reurer
- Department of Surgery, University of Cambridge, and NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
| | - Marco Romano
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom
| | - Sarah Howlett
- Department of Clinical Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Joanne Louise Jones
- Department of Clinical Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Giovanna Lombardi
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom
| | - Kourosh Saeb-Parsy
- Department of Surgery, University of Cambridge, and NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
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Inoue R, Nishiyama K, Li J, Miyashita D, Ono M, Terauchi Y, Shirakawa J. The Feasibility and Applicability of Stem Cell Therapy for the Cure of Type 1 Diabetes. Cells 2021; 10:cells10071589. [PMID: 34202521 PMCID: PMC8304653 DOI: 10.3390/cells10071589] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 06/18/2021] [Accepted: 06/22/2021] [Indexed: 12/25/2022] Open
Abstract
Stem cell therapy using islet-like insulin-producing cells derived from human pluripotent stem cells has the potential to allow patients with type 1 diabetes to withdraw from insulin therapy. However, several issues exist regarding the use of stem cell therapy to treat type 1 diabetes. In this review, we will focus on the following topics: (1) autoimmune responses during the autologous transplantation of stem cell-derived islet cells, (2) a comparison of stem cell therapy with insulin injection therapy, (3) the impact of the islet microenvironment on stem cell-derived islet cells, and (4) the cost-effectiveness of stem cell-derived islet cell transplantation. Based on these various viewpoints, we will discuss what is required to perform stem cell therapy for patients with type 1 diabetes.
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Affiliation(s)
- Ryota Inoue
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 371-8512, Japan; (R.I.); (K.N.); (J.L.)
| | - Kuniyuki Nishiyama
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 371-8512, Japan; (R.I.); (K.N.); (J.L.)
| | - Jinghe Li
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 371-8512, Japan; (R.I.); (K.N.); (J.L.)
| | - Daisuke Miyashita
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (D.M.); (M.O.); (Y.T.)
| | - Masato Ono
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (D.M.); (M.O.); (Y.T.)
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (D.M.); (M.O.); (Y.T.)
| | - Jun Shirakawa
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 371-8512, Japan; (R.I.); (K.N.); (J.L.)
- Correspondence: ; Tel.: +81-27-220-8850
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Madrid M, Sumen C, Aivio S, Saklayen N. Autologous Induced Pluripotent Stem Cell-Based Cell Therapies: Promise, Progress, and Challenges. Curr Protoc 2021; 1:e88. [PMID: 33725407 DOI: 10.1002/cpz1.88] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The promise of human induced pluripotent stem cells (iPSCs) lies in their ability to serve as a starting material for autologous, or patient-specific, stem cell-based therapies. Since the first publications describing the generation of iPSCs from human tissue in 2007, a Phase I/IIa clinical trial testing an autologous iPSC-derived cell therapy has been initiated in the U.S., and several other autologous iPSC-based therapies have advanced through various stages of development. Three single-patient in-human transplants of autologous iPSC-derived cells have taken place worldwide. None of the patients suffered serious adverse events, despite not undergoing immunosuppression. These promising outcomes support the proposed advantage of an autologous approach: a cell therapy product that can engraft without the risk of immune rejection, eliminating the need for immunosuppression and the associated side effects. Despite this advantage, there are currently more allogeneic than autologous iPSC-based cell therapy products in development due to the cost and complexity of scaling out manufacturing for each patient. In this review, we highlight recent progress toward clinical translation of autologous iPSC-based cell therapies. We also highlight technological advancements that would reduce the cost and complexity of autologous iPSC-based cell therapy production, enabling autologous iPSC-based therapies to become a more commonplace treatment modality for patients. © 2021 The Authors.
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Affiliation(s)
| | - Cenk Sumen
- Stemson Therapeutics, San Diego, California
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40
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Peper S, Vo T, Ahuja N, Awad K, Mikos AG, Varanasi V. Bioprinted nanocomposite hydrogels: A proposed approach to functional restoration of skeletal muscle and vascular tissue following volumetric muscle loss. Curr Opin Pharmacol 2021; 58:35-43. [PMID: 33853025 PMCID: PMC8718378 DOI: 10.1016/j.coph.2021.03.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 02/27/2021] [Accepted: 03/11/2021] [Indexed: 01/03/2023]
Abstract
Musculoskeletal conditions are the highest contributor to global disability, accounting for 16% of all ages lived with disability. Volumetric muscle loss (VML) is classified as significant damage to skeletal muscle compartments and motor units, leading to significant tissue loss, functional deficits, and long-term disability. In this review, the current tissue engineering approaches in terms of fabrication techniques, materials, cell sources, and growth factors for enhanced angiogenesis and neuromuscular junction (NMJ) in VML repair, are discussed. Review of results recently published in the literature suggested that bioprinted nanocomposite hydrogels (NC gels) seeded with adult muscle progenitor cells that promote secretion of endogenous vascular growth factors have potential applications in promoting skeletal muscle regeneration, revascularization, and NMJ repair (Figure 1). Despite recent advancements, future research is needed on NC gels and the complex processes underlying vascular infiltration and NMJ repair in VML injuries.
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Affiliation(s)
- Sara Peper
- Bone Muscle Research Center, College of Nursing & Health Innovation, The University of Texas at Arlington, 701 South Nedderman Drive, Arlington, TX, 76019, USA; Department of Bioengineering, College of Engineering, The University of Texas at Arlington, 701 South Nedderman Drive, Box 19138, Arlington, TX, 76019, USA
| | - Thy Vo
- Bone Muscle Research Center, College of Nursing & Health Innovation, The University of Texas at Arlington, 701 South Nedderman Drive, Arlington, TX, 76019, USA; Department of Kinesiology, College of Nursing & Health Innovation, The University of Texas at Arlington, 411 South Nedderman Drive, Box 19407, Arlington, TX, 76019, USA
| | - Neelam Ahuja
- Bone Muscle Research Center, College of Nursing & Health Innovation, The University of Texas at Arlington, 701 South Nedderman Drive, Arlington, TX, 76019, USA; Department of Kinesiology, College of Nursing & Health Innovation, The University of Texas at Arlington, 411 South Nedderman Drive, Box 19407, Arlington, TX, 76019, USA
| | - Kamal Awad
- Bone Muscle Research Center, College of Nursing & Health Innovation, The University of Texas at Arlington, 701 South Nedderman Drive, Arlington, TX, 76019, USA; Department of Materials Science & Engineering, College of Engineering, The University of Texas at Arlington, 701 South Nedderman Drive, Box 19138, Arlington, TX, 76019 & National Research Center, 12622, Egypt
| | - Antonios G Mikos
- Center for Engineering Complex Tissues, Center for Excellence in Tissue Engineering, J.W. Cox Laboratory for Biomedical Engineering, Rice University, P.O. Box 1892, Houston, TX, 77251, USA
| | - Venu Varanasi
- Bone Muscle Research Center, College of Nursing & Health Innovation, The University of Texas at Arlington, 701 South Nedderman Drive, Arlington, TX, 76019, USA; Department of Nursing, College of Nursing & Health Innovation, The University of Texas at Arlington, 411 South Nedderman Drive Box 19407, Arlington, TX, 76019, USA.
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Abstract
Human pluripotent stem cells such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) provide unprecedented opportunities for cell therapies against intractable diseases and injuries. Both ESCs and iPSCs are already being used in clinical trials. However, we continue to encounter practical issues that limit their use, including their inherent properties of tumorigenicity, immunogenicity, and heterogeneity. Here, I review two decades of research aimed at overcoming these three difficulties.
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Sercel AJ, Carlson NM, Patananan AN, Teitell MA. Mitochondrial DNA Dynamics in Reprogramming to Pluripotency. Trends Cell Biol 2021; 31:311-323. [PMID: 33422359 PMCID: PMC7954944 DOI: 10.1016/j.tcb.2020.12.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 12/09/2020] [Accepted: 12/11/2020] [Indexed: 12/20/2022]
Abstract
Mammalian cells, with the exception of erythrocytes, harbor mitochondria, which are organelles that provide energy, intermediate metabolites, and additional activities to sustain cell viability, replication, and function. Mitochondria contain multiple copies of a circular genome called mitochondrial DNA (mtDNA), whose individual sequences are rarely identical (homoplasmy) because of inherited or sporadic mutations that result in multiple mtDNA genotypes (heteroplasmy). Here, we examine potential mechanisms for maintenance or shifts in heteroplasmy that occur in induced pluripotent stem cells (iPSCs) generated by cellular reprogramming, and further discuss manipulations that can alter heteroplasmy to impact stem and differentiated cell performance. This additional insight will assist in developing more robust iPSC-based models of disease and differentiated cell therapies.
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Affiliation(s)
- Alexander J Sercel
- Molecular Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA 90095
| | - Natasha M Carlson
- Department of Biology, California State University Northridge, CA, USA 91330; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA 90095
| | - Alexander N Patananan
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA 90095
| | - Michael A Teitell
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA 90095; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA 90095; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, USA 90095; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA 90095; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research University of California, Los Angeles, Los Angeles, CA, USA 90095; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA 90095; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA 90095.
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43
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Povsic TJ, Gersh BJ. Stem Cells in Cardiovascular Diseases: 30,000-Foot View. Cells 2021; 10:cells10030600. [PMID: 33803227 PMCID: PMC8001267 DOI: 10.3390/cells10030600] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/01/2021] [Accepted: 03/03/2021] [Indexed: 12/15/2022] Open
Abstract
Stem cell and regenerative approaches that might rejuvenate the heart have immense intuitive appeal for the public and scientific communities. Hopes were fueled by initial findings from preclinical models that suggested that easily obtained bone marrow cells might have significant reparative capabilities; however, after initial encouraging pre-clinical and early clinical findings, the realities of clinical development have placed a damper on the field. Clinical trials were often designed to detect exceptionally large treatment effects with modest patient numbers with subsequent disappointing results. First generation approaches were likely overly simplistic and relied on a relatively primitive understanding of regenerative mechanisms and capabilities. Nonetheless, the field continues to move forward and novel cell derivatives, platforms, and cell/device combinations, coupled with a better understanding of the mechanisms that lead to regenerative capabilities in more primitive models and modifications in clinical trial design suggest a brighter future.
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Affiliation(s)
- Thomas J. Povsic
- Department of Medicine, and Duke Clinical Research Institute, Duke University, Durham, NC 27705, USA
- Correspondence:
| | - Bernard J. Gersh
- Department of Cardiovascular Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA;
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44
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Tynecka M, Moniuszko M, Eljaszewicz A. Old Friends with Unexploited Perspectives: Current Advances in Mesenchymal Stem Cell-Based Therapies in Asthma. Stem Cell Rev Rep 2021; 17:1323-1342. [PMID: 33649900 PMCID: PMC7919631 DOI: 10.1007/s12015-021-10137-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2021] [Indexed: 02/07/2023]
Abstract
Mesenchymal stem cells (MSCs) have a great regenerative and immunomodulatory potential that was successfully tested in numerous pre-clinical and clinical studies of various degenerative, hematological and inflammatory disorders. Over the last few decades, substantial immunoregulatory effects of MSC treatment were widely observed in different experimental models of asthma. Therefore, it is tempting to speculate that stem cell-based treatment could become an attractive means to better suppress asthmatic airway inflammation, especially in subjects resistant to currently available anti-inflammatory therapies. In this review, we discuss mechanisms accounting for potent immunosuppressive properties of MSCs and the rationale for their use in asthma. We describe in detail an intriguing interplay between MSCs and other crucial players in the immune system as well as lung microenvironment. Finally, we reveal the potential of MSCs in maintaining airway epithelial integrity and alleviating lung remodeling.
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Affiliation(s)
- Marlena Tynecka
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269, Białystok, Poland
| | - Marcin Moniuszko
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269, Białystok, Poland.
- Department of Allergology and Internal Medicine, Medical University of Bialystok, ul. M. Skłodowskiej-Curie 24A, Białystok, 15-276, Poland.
| | - Andrzej Eljaszewicz
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269, Białystok, Poland.
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45
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Steevens AR, Griesbach MW, You Y, Dutton JR, Low WC, Santi PA. Generation of inner ear sensory neurons using blastocyst complementation in a Neurog1 +/--deficient mouse. Stem Cell Res Ther 2021; 12:122. [PMID: 33579352 PMCID: PMC7881691 DOI: 10.1186/s13287-021-02184-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 01/24/2021] [Indexed: 11/10/2022] Open
Abstract
This research is the first to produce induced pluripotent stem cell-derived inner ear sensory neurons in the Neurog1+/− heterozygote mouse using blastocyst complementation. Additionally, this approach corrected non-sensory deficits associated with Neurog1 heterozygosity, indicating that complementation is specific to endogenous Neurog1 function. This work validates the use of blastocyst complementation as a tool to create novel insight into the function of developmental genes and highlights blastocyst complementation as a potential platform for generating chimeric inner ear cell types that can be transplanted into damaged inner ears to improve hearing.
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Affiliation(s)
- Aleta R Steevens
- Department of Ophthalmology, University of Minnesota, Minneapolis, MN, USA. .,Department of Neurosurgery, University of Minnesota, Minneapolis, MN, USA. .,Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.
| | | | - Yun You
- Mouse Genetics Laboratory, University of Minnesota, Minneapolis, MN, USA
| | - James R Dutton
- Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA
| | - Walter C Low
- Department of Neurosurgery, University of Minnesota, Minneapolis, MN, USA.,Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA
| | - Peter A Santi
- Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.,Department of Otolaryngology, University of Minnesota, Minneapolis, MN, USA
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46
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Verhoeff K, Henschke SJ, Marfil-Garza BA, Dadheech N, Shapiro AMJ. Inducible Pluripotent Stem Cells as a Potential Cure for Diabetes. Cells 2021; 10:cells10020278. [PMID: 33573247 PMCID: PMC7911560 DOI: 10.3390/cells10020278] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 01/22/2021] [Accepted: 01/24/2021] [Indexed: 02/07/2023] Open
Abstract
Over the last century, diabetes has been treated with subcutaneous insulin, a discovery that enabled patients to forego death from hyperglycemia. Despite novel insulin formulations, patients with diabetes continue to suffer morbidity and mortality with unsustainable costs to the health care system. Continuous glucose monitoring, wearable insulin pumps, and closed-loop artificial pancreas systems represent an advance, but still fail to recreate physiologic euglycemia and are not universally available. Islet cell transplantation has evolved into a successful modality for treating a subset of patients with ‘brittle’ diabetes but is limited by organ donor supply and immunosuppression requirements. A novel approach involves generating autologous or immune-protected islet cells for transplant from inducible pluripotent stem cells to eliminate detrimental immune responses and organ supply limitations. In this review, we briefly discuss novel mechanisms for subcutaneous insulin delivery and define their shortfalls. We describe embryological development and physiology of islets to better understand their role in glycemic control and, finally, discuss cell-based therapies for diabetes and barriers to widespread use. In response to these barriers, we present the promise of stem cell therapy, and review the current gaps requiring solutions to enable widespread use of stem cells as a potential cure for diabetes.
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Affiliation(s)
- Kevin Verhoeff
- Department of Surgery, University of Alberta, Edmonton, AB T6G 2B7, Canada;
- Correspondence: ; Tel.: +1-780-984-1836
| | - Sarah J. Henschke
- Department of Emergency Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, Canada;
| | | | - Nidheesh Dadheech
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2B7, Canada;
| | - Andrew Mark James Shapiro
- FRCS (Eng) FRCSC MSM FCAHS, Clinical Islet Transplant Program, Alberta Diabetes Institute, Department of Surgery, Canadian National Transplant Research Program, Edmonton, AB T6G 2B7, Canada;
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47
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Zhang L, Sun H, Chen Y, Wei M, Lee J, Li F, Ling D. Functional nanoassemblies for the diagnosis and therapy of Alzheimer's diseases. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2021; 13:e1696. [PMID: 33463089 DOI: 10.1002/wnan.1696] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 12/23/2020] [Accepted: 12/26/2020] [Indexed: 12/19/2022]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects populations around the world. Many therapeutics have been investigated for AD diagnosis and/or therapy, but the efficacy is largely limited by the poor bioavailability of drugs and by the presence of the blood-brain barrier. Recently, the development of nanomedicines enables efficient drug delivery to the brain, but the complex pathological mechanism of AD prevents them from successful treatment. As a type of advanced nanomedicine, multifunctional nanoassemblies self-assembled from nanoscale imaging or therapeutic agents can simultaneously target multiple pathological factors, showing great potential in the diagnosis and therapy of AD. To help readers better understand this emerging field, in this review, we first introduce the pathological mechanisms and the potential drug candidates of AD, as well as the design strategies of nanoassemblies for improving AD targeting efficiency. Moreover, the progress of dynamic nanoassemblies that can diagnose and/or treat AD in response to the endogenous or exogenous stimuli will be described. Finally, we conclude with our perspectives on the future development in this field. The objective of this review is to outline the latest progress of using nanoassemblies to overcome the complex pathological environment of AD for improved diagnosis and therapy, in hopes of accelerating the future development of intelligent AD nanomedicines. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Diagnostic Tools > in vivo Nanodiagnostics and Imaging.
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Affiliation(s)
- Lingxiao Zhang
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Heng Sun
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Ying Chen
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Min Wei
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Jiyoung Lee
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Fangyuan Li
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Key Laboratory of Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou, China
| | - Daishun Ling
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Key Laboratory of Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou, China
- National Center for Translational Medicine, Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, China
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48
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Frederiksen HR, Doehn U, Tveden-Nyborg P, Freude KK. Non-immunogenic Induced Pluripotent Stem Cells, a Promising Way Forward for Allogenic Transplantations for Neurological Disorders. Front Genome Ed 2021; 2:623717. [PMID: 34713244 PMCID: PMC8525385 DOI: 10.3389/fgeed.2020.623717] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/08/2020] [Indexed: 12/19/2022] Open
Abstract
Neurological disorder is a general term used for diseases affecting the function of the brain and nervous system. Those include a broad range of diseases from developmental disorders (e.g., Autism) over injury related disorders (e.g., stroke and brain tumors) to age related neurodegeneration (e.g., Alzheimer's disease), affecting up to 1 billion people worldwide. For most of those disorders, no curative treatment exists leaving symptomatic treatment as the primary mean of alleviation. Human induced pluripotent stem cells (hiPSC) in combination with animal models have been instrumental to foster our understanding of underlying disease mechanisms in the brain. Of specific interest are patient derived hiPSC which allow for targeted gene editing in the cases of known mutations. Such personalized treatment would include (1) acquisition of primary cells from the patient, (2) reprogramming of those into hiPSC via non-integrative methods, (3) corrective intervention via CRISPR-Cas9 gene editing of mutations, (4) quality control to ensure successful correction and absence of off-target effects, and (5) subsequent transplantation of hiPSC or pre-differentiated precursor cells for cell replacement therapies. This would be the ideal scenario but it is time consuming and expensive. Therefore, it would be of great benefit if transplanted hiPSC could be modulated to become invisible to the recipient's immune system, avoiding graft rejection and allowing for allogenic transplantations. This review will focus on the current status of gene editing to generate non-immunogenic hiPSC and how these cells can be used to treat neurological disorders by using cell replacement therapy. By providing an overview of current limitations and challenges in stem cell replacement therapies and the treatment of neurological disorders, this review outlines how gene editing and non-immunogenic hiPSC can contribute and pave the road for new therapeutic advances. Finally, the combination of using non-immunogenic hiPSC and in vivo animal modeling will highlight the importance of models with translational value for safety efficacy testing; before embarking on human trials.
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Affiliation(s)
- Henriette Reventlow Frederiksen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ulrik Doehn
- Stem Cell Discovery, Novo Nordisk A/S, Måløv, Denmark
| | - Pernille Tveden-Nyborg
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kristine K. Freude
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- *Correspondence: Kristine K. Freude
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49
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Ishigaki H, Pham VL, Terai J, Sasamura T, Nguyen CT, Ishida H, Okahara J, Kaneko S, Shiina T, Nakayama M, Itoh Y, Ogasawara K. No Tumorigenicity of Allogeneic Induced Pluripotent Stem Cells in Major Histocompatibility Complex-matched Cynomolgus Macaques. Cell Transplant 2021; 30:963689721992066. [PMID: 33588604 PMCID: PMC7894586 DOI: 10.1177/0963689721992066] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 12/11/2020] [Accepted: 01/12/2021] [Indexed: 12/14/2022] Open
Abstract
Tumorigenicity of induced pluripotent stem cells (iPSCs) is anticipated when cells derived from iPSCs are transplanted. It has been reported that iPSCs formed a teratoma in vivo in autologous transplantation in a nonhuman primate model without immunosuppression. However, there has been no study on tumorigenicity in major histocompatibility complex (MHC)-matched allogeneic iPSC transplantation with immune-competent hosts. To examine the tumorigenicity of allogeneic iPSCs, we generated four iPSC clones carrying a homozygous haplotype of the MHC. Two clones were derived from female fibroblasts by using a retrovirus and the other two clones were derived from male peripheral blood mononuclear cells by using Sendai virus (episomal approach). The iPSC clones were transplanted into allogenic MHC-matched immune-competent cynomolgus macaques. After transplantation of the iPSCs into subcutaneous tissue of an MHC-matched female macaque and into four testes of two MHC-matched male macaques, histological analysis showed no tumor, inflammation, or regenerative change in the excised tissues 3 months after transplantation, despite the results that iPSCs formed teratomas in immune-deficient mice and in autologous transplantation as previously reported. The results in the present study suggest that there is no tumorigenicity of iPSCs in MHC-matched allogeneic transplantation in clinical application.
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Affiliation(s)
- Hirohito Ishigaki
- Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Van Loi Pham
- Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan
- Biomolecular and Genetic Unit, Department of Hematology, Choray Hospital, Ho Chi Minh City, Vietnam
| | - Jun Terai
- Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Takako Sasamura
- Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Cong Thanh Nguyen
- Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Hideaki Ishida
- Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Junko Okahara
- Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan
| | - Shin Kaneko
- Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Takashi Shiina
- Division of Basic Medical Science and Molecular Medicine, Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Misako Nakayama
- Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Yasushi Itoh
- Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Kazumasa Ogasawara
- Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan
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50
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Strategies for Cancer Immunotherapy Using Induced Pluripotency Stem Cells-Based Vaccines. Cancers (Basel) 2020; 12:cancers12123581. [PMID: 33266109 PMCID: PMC7760556 DOI: 10.3390/cancers12123581] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/24/2020] [Accepted: 11/27/2020] [Indexed: 12/14/2022] Open
Abstract
Despite improvements in cancer therapy, metastatic solid tumors remain largely incurable. Immunotherapy has emerged as a pioneering and promising approach for cancer therapy and management, and in particular intended for advanced tumors unresponsive to current therapeutics. In cancer immunotherapy, components of the immune system are exploited to eliminate cancer cells and treat patients. The recent clinical successes of immune checkpoint blockade and chimeric antigen receptor T cell therapies represent a turning point in cancer treatment. Despite their potential success, current approaches depend on efficient tumor antigen presentation which are often inaccessible, and most tumors turn refractory to current immunotherapy. Patient-derived induced pluripotent stem cells (iPSCs) have been shown to share several characteristics with cancer (stem) cells (CSCs), eliciting a specific anti-tumoral response when injected in rodent cancer models. Indeed, artificial cellular reprogramming has been widely compared to the biogenesis of CSCs. Here, we will discuss the state-of-the-art on the potential implication of cellular reprogramming and iPSCs for the design of patient-specific immunotherapeutic strategies, debating the similarities between iPSCs and cancer cells and introducing potential strategies that could enhance the efficiency and therapeutic potential of iPSCs-based cancer vaccines.
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