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Ortuño-Costela MC, Pinzani M, Vallier L. Cell therapy for liver disorders: past, present and future. Nat Rev Gastroenterol Hepatol 2025; 22:329-342. [PMID: 40102584 DOI: 10.1038/s41575-025-01050-2] [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] [Accepted: 02/11/2025] [Indexed: 03/20/2025]
Abstract
The liver fulfils a plethora of vital functions and, due to their importance, liver dysfunction has life-threatening consequences. Liver disorders currently account for more than two million deaths annually worldwide and can be classified broadly into three groups, considering their onset and aetiology, as acute liver diseases, inherited metabolic disorders and chronic liver diseases. In the most advanced and severe forms leading to liver failure, liver transplantation is the only treatment available, which has many associated drawbacks, including a shortage of organ donors. Cell therapy via fully mature cell transplantation is an advantageous alternative that may be able to restore a damaged organ's functionality or serve as a bridge until regeneration can occur. Pioneering work has shown that transplanting adult hepatocytes can support liver recovery. However, primary hepatocytes cannot be grown extensively in vitro as they rapidly lose their metabolic activity. Therefore, different cell sources are currently being tested as alternatives to primary cells. Human pluripotent stem cell-derived cells, chemically induced liver progenitors, or 'liver' organoids, hold great promise for developing new cell therapies for acute and chronic liver diseases. This Review focuses on the advantages and drawbacks of distinct cell sources and the relative strategies to address different therapeutic needs in distinct liver diseases.
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Affiliation(s)
- M Carmen Ortuño-Costela
- Berlin Institute of Health, BIH Centre for Regenerative Therapies, Charité-Universitätsmedizin, Berlin, Germany
- Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Massimo Pinzani
- University College London Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, London, UK
- University of Pittsburgh Medical Center-Mediterranean Institute for Transplantation and Highly Specialized Therapies (UPMC-ISMETT), Palermo, Italy
| | - Ludovic Vallier
- Berlin Institute of Health, BIH Centre for Regenerative Therapies, Charité-Universitätsmedizin, Berlin, Germany.
- Max Planck Institute for Molecular Genetics, Berlin, Germany.
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2
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Maiers M, Sullivan S, McClain C, Leonhard-Melief C, Turner ML, Turner D. Harnessing global HLA data for enhanced patient matching in iPSC haplobanks. Cytotherapy 2025; 27:300-306. [PMID: 39718520 DOI: 10.1016/j.jcyt.2024.11.001] [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: 09/23/2024] [Revised: 10/24/2024] [Accepted: 11/03/2024] [Indexed: 12/25/2024]
Abstract
BACKGROUND Several countries have either developed or are developing national induced pluripotent stem cell (iPSC) banks of cell lines derived from donors with HLA homozygous genotypes (two identical haplotypes) prevalent in their local populations to provide immune matched tissues and cells to support regenerative medicine therapies. This 'haplobank' approach relies on knowledge of the HLA genotypes of the population to identify the most beneficial haplotypes for patient coverage, and ultimately identify donors or cord blood units carrying two copies of the target haplotype. AIMS A potentially more efficient alternative to a national bank approach is to assess the haplotypes required to provide global patient coverage and to produce a single, global haplobank. Toward that end, we have developed an algorithm to prioritize HLA haplotypes that optimize coverage across the global population. METHODS We analyzed data from eighteen countries participating in the Global Alliance for iPS Therapy (GAiT). A representative pool of HLA genotypes, reflecting the HLA of patients, was derived by sampling from each country's WMDA hematopoietic stem cell donor registry, or surrogate population. An algorithm was created based on HLA-A, -B and -DRB1 haplotype homozygous types with population HLA matching coverage defined by the absence of Host versus Graft (HvG) mismatches at these loci. HLA matching coverage was determined by iteratively selecting HLA haplotypes that provide the largest coverage against patient HLA genotypes sampled from the same population, excluding genotypes compatible with previous iterations. RESULTS The top 10 haplotypes for each of the 18 countries were identified with patient coverage ranging from 19.5% in Brazil to 63.8% in Japan, with a mean coverage of 33.3%. In a 'global' model, utilizing the 180 most frequent haplotypes across all 18 populations (equivalent to 10 lines per country), the patient coverage ranged from 54.6% in India to 81.7% in Sweden, with a mean of 68.4%. Our findings demonstrate that global collaboration could more than double the potential for patient HLA matching coverage. CONCLUSIONS Interrogation of unrelated hematopoietic stem cell donor registry and cord blood bank HLA data demonstrated that HLA-A, -B, and -DRB1 homozygous donors for the top 180 global haplotypes are widely available. These results show that a globally coordinated strategy for haplobanking would reduce redundancy and allow more patients to be treated with the same investment.
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Affiliation(s)
- Martin Maiers
- CIBMTR (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, Minnesota, USA.
| | - Stephen Sullivan
- iPSirius, Paris, France; Lindville Bio, Edinburgh, UK; Global Alliance for iPSC Therapies, Jack Copland Centre, Heriot-Watt Research Park, Edinburgh, UK
| | | | - Christina Leonhard-Melief
- CIBMTR (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, Minnesota, USA
| | - Marc L Turner
- Scottish National Blood Transfusion Service, Edinburgh, UK; Global Alliance for iPSC Therapies, Jack Copland Centre, Heriot-Watt Research Park, Edinburgh, UK
| | - David Turner
- Scottish National Blood Transfusion Service, Edinburgh, UK; Global Alliance for iPSC Therapies, Jack Copland Centre, Heriot-Watt Research Park, Edinburgh, UK
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Sugihara HY, Okamoto R, Mizutani T. Intestinal organoids: The path towards clinical application. Eur J Cell Biol 2025; 104:151474. [PMID: 39740324 DOI: 10.1016/j.ejcb.2024.151474] [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: 08/30/2024] [Revised: 11/14/2024] [Accepted: 11/17/2024] [Indexed: 01/02/2025] Open
Abstract
Organoids have revolutionized the whole field of biology with their ability to model complex three-dimensional human organs in vitro. Intestinal organoids were especially consequential as the first successful long-term culture of intestinal stem cells, which raised hopes for translational medical applications. Despite significant contributions to basic research, challenges remain to develop intestinal organoids into clinical tools for diagnosis, prognosis, and therapy. In this review, we outline the current state of translational research involving adult stem cell and pluripotent stem cell derived intestinal organoids, highlighting the advances and limitations in disease modeling, drug-screening, personalized medicine, and stem cell therapy. Preclinical studies have demonstrated a remarkable functional recapitulation of infectious and genetic diseases, and there is mounting evidence for the reliability of intestinal organoids as a patient-specific avatar. Breakthroughs now allow the generation of structurally and cellularly complex intestinal models to better capture a wider range of intestinal pathophysiology. As the field develops and evolves, there is a need for standardized frameworks for generation, culture, storage, and analysis of intestinal organoids to ensure reproducibility, comparability, and interpretability of these preclinical and clinical studies to ultimately enable clinical translation.
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Affiliation(s)
- Hady Yuki Sugihara
- Department of Gastroenterology and Hepatology, Institute of Science Tokyo, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Institute of Science Tokyo, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Tomohiro Mizutani
- Department of Gastroenterology and Hepatology, Institute of Science Tokyo, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
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4
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Sorrentino FS, Di Terlizzi P, De Rosa F, Salati C, Spadea L, Gagliano C, Musa M, Zeppieri M. New frontiers in retinal transplantation. World J Transplant 2024; 14:97690. [PMID: 39697450 PMCID: PMC11438945 DOI: 10.5500/wjt.v14.i4.97690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 07/22/2024] [Accepted: 07/24/2024] [Indexed: 09/20/2024] Open
Abstract
New frontiers about retinal cell transplantation for retinal degenerative diseases start from the idea that acting on stem cells can help regenerate retinal layers and establish new synapses among retinal cells. Deficiency or alterations of synaptic input and neurotrophic factors result in trans-neuronal degeneration of the inner retinal cells. Thus, the disruption of photoreceptors takes place. However, even in advanced forms of retinal degeneration, a good percentage of the ganglion cells and the inner nuclear layer neurons remain intact. This phenomenon provides evidence for obtaining retinal circuitry through the transplantation of photoreceptors into the subretinal region. The eye is regarded as an optimal organ for cell transplantation because of its immunological privilege and the relatively small number of cells collaborating to carry out visual activities. The eyeball's immunological privilege, characterized by the suppression of delayed-type hypersensitivity responses in ocular tissues, is responsible for the low rate of graft rejection in transplant patients. The main discoveries highlight the capacity of embryonic stem cells (ESCs) and induced pluripotent stem cells to regenerate damaged retinal regions. Recent progress has shown significant enhancements in transplant procedures and results. The research also explores the ethical ramifications linked to the utilization of stem cells, emphasizing the ongoing issue surrounding ESCs. The analysis centers on recent breakthroughs, including the fabrication of three-dimensional retinal organoids and the innovation of scaffolding for cell transportation. Moreover, researchers are currently assessing the possibility of CRISPR and other advanced gene editing technologies to enhance the outcomes of retinal transplantation. The widespread use of universally recognized safe surgical and imaging methods enables retinal transplantation and monitoring of transplanted cell growth toward the correct location. Currently, most therapy approaches are in the first phases of development and necessitate further research, including both pre-clinical and clinical trials, to attain favorable visual results for individuals suffering from retinal degenerative illnesses.
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Affiliation(s)
| | - Patrick Di Terlizzi
- Department of Surgical Sciences, Unit of Ophthalmology, Ospedale Maggiore, Bologna 40100, Italy
| | - Francesco De Rosa
- Department of Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori”, Meldola 47014, Italy
| | - Carlo Salati
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
| | - Leopoldo Spadea
- Eye Clinic, Policlinico Umberto I, "Sapienza" University of Rome, Rome 00142, Italy
| | - Caterina Gagliano
- Department of Medicine and Surgery, University of Enna "Kore", Enna 94100, Italy
- Eye Clinic, Catania University San Marco Hospital, Catania 95121, Italy
| | - Mutali Musa
- Department of Optometry, University of Benin, Benin 300283, Nigeria
- Department of Ophthalmology, Centre for Sight Africa, Nkpor, Onitsha 434112, Nigeria
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
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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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Frederiksen HR, Glantz A, Vøls KK, Skov S, Tveden-Nyborg P, Freude K, Doehn U. CRISPR-Cas9 immune-evasive hESCs are rejected following transplantation into immunocompetent mice. Front Genome Ed 2024; 6:1403395. [PMID: 38863835 PMCID: PMC11165197 DOI: 10.3389/fgeed.2024.1403395] [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: 03/19/2024] [Accepted: 05/07/2024] [Indexed: 06/13/2024] Open
Abstract
Although current stem cell therapies exhibit promising potential, the extended process of employing autologous cells and the necessity for donor-host matching to avert the rejection of transplanted cells significantly limit the widespread applicability of these treatments. It would be highly advantageous to generate a pluripotent universal donor stem cell line that is immune-evasive and, therefore, not restricted by the individual's immune system, enabling unlimited application within cell replacement therapies. Before such immune-evasive stem cells can be moved forward to clinical trials, in vivo testing via transplantation experiments in immune-competent animals would be a favorable approach preceding preclinical testing. By using human stem cells in immune competent animals, results will be more translatable to a clinical setting, as no parts of the immune system have been altered, although in a xenogeneic setting. In this way, immune evasiveness, cell survival, and unwanted proliferative effects can be assessed before clinical trials in humans. The current study presents the generation and characterization of three human embryonic stem cell lines (hESCs) for xenogeneic transplantation in immune-competent mice. The major histocompatibility complexes I- and II-encoding genes, B2M and CIITA, have been deleted from the hESCs using CRISPR-Cas9-targeted gene replacement strategies and knockout. B2M was knocked out by the insertion of murine CD47. Human-secreted embryonic alkaline phosphatase (hSEAP) was inserted in a safe harbor site to track cells in vivo. The edited hESCs maintained their pluripotency, karyotypic normality, and stable expression of murine CD47 and hSEAP in vitro. In vivo transplantation of hESCs into immune-competent BALB/c mice was successfully monitored by measuring hSEAP in blood samples. Nevertheless, transplantation of immune-evasive hESCs resulted in complete rejection within 11 days, with clear immune infiltration of T-cells on day 8. Our results reveal that knockout of B2M and CIITA together with species-specific expression of CD47 are insufficient to prevent rejection in an immune-competent and xenogeneic context.
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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
| | | | | | - Søren Skov
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Pernille Tveden-Nyborg
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kristine Freude
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ulrik Doehn
- Cell Therapy Research, Novo Nordisk A/S, Maaloev, Denmark
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7
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Harding J, Vintersten-Nagy K, Yang H, Tang JK, Shutova M, Jong ED, Lee JH, Massumi M, Oussenko T, Izadifar Z, Zhang P, Rogers IM, Wheeler MB, Lye SJ, Sung HK, Li C, Izadifar M, Nagy A. Immune-privileged tissues formed from immunologically cloaked mouse embryonic stem cells survive long term in allogeneic hosts. Nat Biomed Eng 2024; 8:427-442. [PMID: 37996616 PMCID: PMC11087263 DOI: 10.1038/s41551-023-01133-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 09/30/2023] [Indexed: 11/25/2023]
Abstract
The immunogenicity of transplanted allogeneic cells and tissues is a major hurdle to the advancement of cell therapies. Here we show that the overexpression of eight immunomodulatory transgenes (Pdl1, Cd200, Cd47, H2-M3, Fasl, Serpinb9, Ccl21 and Mfge8) in mouse embryonic stem cells (mESCs) is sufficient to immunologically 'cloak' the cells as well as tissues derived from them, allowing their survival for months in outbred and allogeneic inbred recipients. Overexpression of the human orthologues of these genes in human ESCs abolished the activation of allogeneic human peripheral blood mononuclear cells and their inflammatory responses. Moreover, by using the previously reported FailSafe transgene system, which transcriptionally links a gene essential for cell division with an inducible and cell-proliferation-dependent kill switch, we generated cloaked tissues from mESCs that served as immune-privileged subcutaneous sites that protected uncloaked allogeneic and xenogeneic cells from rejection in immune-competent hosts. The combination of cloaking and FailSafe technologies may allow for the generation of safe and allogeneically accepted cell lines and off-the-shelf cell products.
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Affiliation(s)
- Jeffrey Harding
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Kristina Vintersten-Nagy
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Huijuan Yang
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Jean Kit Tang
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Maria Shutova
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Eric D Jong
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Ju Hee Lee
- Translational Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Mohammad Massumi
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Tatiana Oussenko
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Zohreh Izadifar
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Puzheng Zhang
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Ian M Rogers
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada
| | - Michael B Wheeler
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, Toronto, Ontario, Canada
| | - Stephen J Lye
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada
| | - Hoon-Ki Sung
- Translational Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - ChengJin Li
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Mohammad Izadifar
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Andras Nagy
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
- Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada.
- Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia.
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Ma C, Cao H, Sun Z, Deng Q, Liu W, Xin Y, Qiao S, Cen J, Shu Y, Qi K, Han L, Zhang L, Pan G. CD47 and PD-L1 overexpression in proliferating human hepatocytes attenuated immune responses and ameliorated acute liver injury in mice. Am J Transplant 2023; 23:1832-1844. [PMID: 37532180 DOI: 10.1016/j.ajt.2023.07.020] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 06/18/2023] [Accepted: 07/26/2023] [Indexed: 08/04/2023]
Abstract
Hepatocyte transplantation has the potential to treat acute liver failure and correct liver-based metabolic disorders. Proliferating human hepatocytes (ProliHHs) provide a large-scale source as an alternative to primary human hepatocytes. However, host rejection led to inefficient graft survival and function, which hindered the clinical application of cell therapy. Herein, we employed the lentiviral system to overexpress immunomodulatory factors programmed death-ligand 1 (cluster of differentiation 274) (CD274) and cluster of differentiation 47 (CD47) in ProliHHs. CD47+274 overexpression inhibited macrophage and T cell responses in vitro. After transplantation into mice via the spleen without immunosuppression, CD47+274 ProliHHs accumulation in the liver significantly increased for 48 hours compared with ProliHHs. Consistent with the in vitro results, CD47+274 ProliHHs were less aggregated and infiltrated by macrophages and also recruited fewer T cells in the liver. Seven days after transplantation, the human albumin level of engineered ProliHHs doubled compared with control group. CD47+274 ProliHHs further ameliorated the liver injury induced using concanavalin A. Overall, our results suggested CD47+274 overexpression reduced innate and adaptive immune responses during hepatocyte transplantation, and the survival rate and graft function of transplanted hepatocyte-like cells were all significantly improved.
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Affiliation(s)
- Chen Ma
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Huiying Cao
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Zhen Sun
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Science, Beijing, China; School of Life Science and Technology, Shanghai Tech University, Shanghai, China
| | - Qiangqiang Deng
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Wenjing Liu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, China
| | - Yingying Xin
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Shida Qiao
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Jin Cen
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Science, Beijing, China
| | - Yajing Shu
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Science, Beijing, China
| | - Kai Qi
- Shanghai Hexaell Biotech Co., Ltd, Shanghai, China
| | - Li Han
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Ludi Zhang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Science, Beijing, China.
| | - Guoyu Pan
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
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9
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Endo R, Sugimoto S, Shirosaki K, Kato H, Wada M, Kanai T, Sato T. Clinical challenges of short bowel syndrome and the path forward for organoid-based regenerative medicine. Regen Ther 2023; 24:64-73. [PMID: 37868721 PMCID: PMC10584670 DOI: 10.1016/j.reth.2023.06.001] [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: 03/31/2023] [Revised: 05/25/2023] [Accepted: 06/01/2023] [Indexed: 10/24/2023] Open
Abstract
Short bowel syndrome (SBS) is a rare condition, the main symptom of which is malabsorption following extensive resection of the small intestine. Treatment for SBS is mainly supportive, consisting of supplementation, prevention and treatment of complications, and promotion of intestinal adaptation. While development of parenteral nutrition and drugs promoting intestinal adaptation has improved clinical outcomes, the prognosis of patients with SBS remains poor. Intestinal transplantation is the only curative therapy but its outcome is unsatisfactory. In the absence of definitive therapy, novel treatment is urgently needed. With the advent of intestinal organoids, research on the intestine has developed remarkably in recent years. Concepts such as the "tissue-engineered small intestine" and "small intestinalized colon," which create a functional small intestine by combining organoids with other technologies, are potentially novel regenerative therapeutic approaches for SBS. Although they are still under development and there are substantial issues to be resolved, the problems that have prevented establishment of the complex function and structure of the small intestine are gradually being overcome. This review discusses the current treatments for SBS, the fundamentals of the intestine and organoids, the current status of these new technologies, and future perspectives.
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Affiliation(s)
- Ryoma Endo
- Department of Organoid Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
- Department of Pediatric Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Shinya Sugimoto
- Department of Organoid Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Koji Shirosaki
- Department of Organoid Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Hirochika Kato
- Department of Organoid Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
- Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Motoshi Wada
- Department of Pediatric Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Toshiro Sato
- Department of Organoid Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
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Soucy JR, Aguzzi EA, Cho J, Gilhooley MJ, Keuthan C, Luo Z, Monavarfeshani A, Saleem MA, Wang XW, Wohlschlegel J, Baranov P, Di Polo A, Fortune B, Gokoffski KK, Goldberg JL, Guido W, Kolodkin AL, Mason CA, Ou Y, Reh TA, Ross AG, Samuels BC, Welsbie D, Zack DJ, Johnson TV. Retinal ganglion cell repopulation for vision restoration in optic neuropathy: a roadmap from the RReSTORe Consortium. Mol Neurodegener 2023; 18:64. [PMID: 37735444 PMCID: PMC10514988 DOI: 10.1186/s13024-023-00655-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 09/07/2023] [Indexed: 09/23/2023] Open
Abstract
Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system's limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortium's efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies.
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Affiliation(s)
- Jonathan R Soucy
- Department of Ophthalmology, Schepens Eye Research Institute of Mass. Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Erika A Aguzzi
- The Institute of Ophthalmology, University College London, London, England, UK
| | - Julie Cho
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Michael James Gilhooley
- The Institute of Ophthalmology, University College London, London, England, UK
- Moorfields Eye Hospital, London, England, UK
| | - Casey Keuthan
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ziming Luo
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Aboozar Monavarfeshani
- Center for Brain Science and Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA
- Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA
| | - Meher A Saleem
- Bascom Palmer Eye Institute, University of Miami Health System, Miami, FL, USA
| | - Xue-Wei Wang
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Petr Baranov
- Department of Ophthalmology, Schepens Eye Research Institute of Mass. Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Adriana Di Polo
- Department of Neuroscience, University of Montreal, Montreal, QC, Canada
- University of Montreal Hospital Research Centre, Montreal, QC, Canada
| | - Brad Fortune
- Discoveries in Sight Research Laboratories, Devers Eye Institute and Legacy Research Institute, Legacy Health, Portland, OR, USA
| | - Kimberly K Gokoffski
- Department of Ophthalmology, Roski Eye Institute, University of Southern California, Los Angeles, CA, USA
| | - Jeffrey L Goldberg
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
| | - William Guido
- Department of Anatomical Sciences and Neurobiology, School of Medicine, University of Louisville, Louisville, KY, USA
| | - Alex L Kolodkin
- The Solomon H Snyder, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Carol A Mason
- Departments of Pathology and Cell Biology, Neuroscience, and Ophthalmology, College of Physicians and Surgeons, Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA
| | - Yvonne Ou
- Department of Ophthalmology, University of California, San Francisco, CA, USA
| | - Thomas A Reh
- Department of Biological Structure, University of Washington, Seattle, WA, USA
| | - Ahmara G Ross
- Departments of Ophthalmology and Neurology, University of Pennsylvania, Philadelphia, PA, USA
| | - Brian C Samuels
- Department of Ophthalmology and Visual Sciences, Callahan Eye Hospital, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Derek Welsbie
- Shiley Eye Institute and Viterbi Family Department of Ophthalmology, University of California, San Diego, CA, USA
| | - Donald J Zack
- Glaucoma Center of Excellence, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, 21287 MD, USA
- Departments of Neuroscience, Molecular Biology & Genetics, and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Thomas V Johnson
- Departments of Neuroscience, Molecular Biology & Genetics, and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Cellular & Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, 21287 MD, USA.
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Rizano A, Margiana R, Supardi S, Narulita P. Exploring the future potential of mesenchymal stem/stromal cells and their derivatives to support assisted reproductive technology for female infertility applications. Hum Cell 2023; 36:1604-1619. [PMID: 37407748 DOI: 10.1007/s13577-023-00941-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 06/16/2023] [Indexed: 07/07/2023]
Abstract
Women's infertility impacts the quality of life of both patients and couples and has multifaceted dimensions that increase the number of challenges associated with female infertility and how to face them. Female reproductive disorders, such as premature ovarian failure (POF), endometriosis, Asherman syndrome (AS), polycystic ovary syndrome (PCOS), and preeclampsia, can stimulate infertility. In the last decade, translational medicine has advanced, and scientists are focusing on infertility therapy with innovative attitudes. Recent investigations have suggested that stem cell treatments could be safe and effective. Stem cell therapy has established a novel method for treating women's infertility as part of a regeneration approach. The chief properties and potential of mesenchymal stem/stromal cells (MSCs) in the future of women's infertility should be considered by researchers. Due to their high abundance, great ability to self-renew, and high differentiation capacity, as well as less ethical concerns, MSC-based therapy has been found to be an effective alternative strategy to the previous methods for treating female infertility, such as intrauterine insemination, in vitro fertilization, medicines, and surgical procedures. These types of stem cells exert their beneficial role by releasing active mediators, promoting cell homing, and contributing to immune modulation. Here we first provide an overview of MSCs and their crucial roles in both biological and immunological processes. The next large chapter covers current preclinical and clinical studies on the application of MSCs to treat various female reproductive disorders. Finally, we deliberate on the extant challenges that hinder the application of MSCs in female infertility and suggest plausible measures to alleviate these impediments.
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Affiliation(s)
- Andrew Rizano
- Department of Medical Biology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Ria Margiana
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia.
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
- Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
- Indonesia General Academic Hospital, Depok, Indonesia.
- Ciptomangunkusumo General Academic Hospital, Jakarta, Indonesia.
| | - Supardi Supardi
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Pety Narulita
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
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12
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Nakanishi A, Toyama S, Onozato D, Watanabe C, Hashita T, Iwao T, Matsunaga T. Effects of human induced pluripotent stem cell-derived intestinal organoids on colitis-model mice. Regen Ther 2022; 21:351-361. [PMID: 36161099 PMCID: PMC9471335 DOI: 10.1016/j.reth.2022.08.004] [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: 04/14/2022] [Revised: 07/20/2022] [Accepted: 08/09/2022] [Indexed: 11/25/2022] Open
Abstract
Introduction Ulcerative colitis (UC) is an inflammatory bowel disease characterized by repeated remissions and relapses. Immunosuppressive drugs have facilitated the induction and maintenance of remission in many patients with UC. However, immunosuppressive drugs cannot directly repair impaired intestinal mucosa and are insufficient for preventing relapse. Therefore, new treatment approaches to repair the damaged epithelium in UC have been attempted through the transplantation of intestinal organoids, which can be differentiated into mucosa by embedding in Matrigel, generated from patient-derived intestinal stem cells. The method, however, poses the challenge of yielding sufficient cells for UC therapy, and patient-derived cells might already have acquired pathological changes. In contrast, human induced pluripotent stem (iPS) cells generated from healthy individuals are infinitely proliferated and can be differentiated into target cells. Recently developed human iPS cell-derived intestinal organoids (HIOs) aim to generate organoids that closely resemble the adult intestine. However, no study till date has reported HIOs injected into in vivo inflammatory models, and it remains unclear whether HIOs with cells that closely resemble the adult intestine or with intestinal stem cells retain the better ability to repair tissue in colitis. Methods We generated two types of HIOs via suspension culture with and without small-molecule compounds: HIOs that include predominantly more intestinal stem cells [HIO (A)] and those that include predominantly more intestinal epithelial and secretory cells [HIO (B)]. We examined whether the generated HIOs engrafted in vivo and compared their ability to accelerate recovery of the damaged tissue. Results Findings showed that the HIOs expressed intestinal-specific markers such as caudal-type homeobox 2 (CDX2) and villin, and HIOs engrafted under the kidney capsules of mice. We then injected HIOs into colitis-model mice and found that the weight and clinical score of the mice injected with HIO (A) recovered earlier than that of the mice in the sham group. Further, the production of mucus and the expression of cell proliferation markers and tight junction proteins in the colon tissues of the HIO (A) group were restored to levels similar to those observed in healthy mice. However, neither HIO (A) nor HIO (B) could be engrafted into the colon. Conclusions Effective cell therapy should directly repair tissue by engraftment at the site of injury. However, the difference in organoid property impacting the rate of tissue repair in transplantation without engraftment observed in the current study should be considered a critical consideration in the development of regenerative medicine using iPS-derived organoids.
Human iPS cell-derived intestinal organoids were generated via suspension culture. The effects of two types of intestinal organoids in vivo were compared. Intestinal organoids were engrafted under mouse kidney capsules. Intestinal organoids promoted mucosal healing in acute colitis-model mice. Organoids with a higher gene expression of intestinal stem cell had higher effects.
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Key Words
- 5-aza, 5-aza-2′-deoxycytidine
- A-83-01, 3-(6-methyl-2-pyridinyl)-N-phenyl-4-(4-quinolinyl)-1H-pyrazole-1-carbothioamide
- CDX2, caudal-type homeobox 2
- CHGA, chromogranin A
- Cell therapy
- DAPI, 4′,6-diamidino-2-phenylindole
- DAPT, N-[(3,5-difluorophenyl)acetyl]-L-alanyl-2-phenyl-1,1-dime-thylethyl ester-glycine
- DSS, dextran sodium sulfate
- FBS, fetal bovine serum
- HIO, human induced pluripotent stem cell-derived intestinal organoid
- HLA, human leukocyte antigen
- HPRT, hypoxanthine phosphoribosyltransferase
- Human induced pluripotent stem cell
- Inflammatory bowel disease
- Intestinal organoid
- LGR5, leucine-rich repeat-containing G-protein-coupled receptor 5
- MUC2, mucin 2
- NSG, NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ
- OLFM4, olfactomedin 4
- PBS, phosphate-buffered saline
- PD98059, 2-(2-amino-3-methoxyphenyl)4-H-1-benzopyran-4-one
- SCID-Beige, CB17.Cg-PrkdcscidLystbg-J/CrlCrlj
- Suspension culture
- UC, ulcerative colitis
- Ulcerative colitis
- VIL1, villin 1
- Y-27632, (+)-(R)-trans-4-(1-amino-ethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride
- iPS, induced pluripotent stem
- qPCR, quantitative polymerase chain reaction
- α-SMA, α-smooth muscle actin
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Affiliation(s)
- Anna Nakanishi
- Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
| | - Satoshi Toyama
- Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
| | - Daichi Onozato
- Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
| | - Chihiro Watanabe
- Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
| | - Tadahiro Hashita
- Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.,Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
| | - Takahiro Iwao
- Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.,Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
| | - Tamihide Matsunaga
- Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.,Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
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13
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Fang J, Li JJ, Zhong X, Zhou Y, Lee RJ, Cheng K, Li S. Engineering stem cell therapeutics for cardiac repair. J Mol Cell Cardiol 2022; 171:56-68. [PMID: 35863282 DOI: 10.1016/j.yjmcc.2022.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 05/18/2022] [Accepted: 06/25/2022] [Indexed: 10/17/2022]
Abstract
Cardiovascular disease is the leading cause of death in the world. Stem cell-based therapies have been widely investigated for cardiac regeneration in patients with heart failure or myocardial infarction (MI) and surged ahead on multiple fronts over the past two decades. To enhance cellular therapy for cardiac regeneration, numerous engineering techniques have been explored to engineer cells, develop novel scaffolds, make constructs, and deliver cells or their derivatives. This review summarizes the state-of-art stem cell-based therapeutics for cardiac regeneration and discusses the emerged bioengineering approaches toward the enhancement of therapeutic efficacy of stem cell therapies in cardiac repair. We cover the topics in stem cell source and engineering, followed by stem cell-based therapies such as cell aggregates and cell sheets, and biomaterial-mediated stem cell therapies such as stem cell delivery with injectable hydrogel, three-dimensional scaffolds, and microneedle patches. Finally, we discuss future directions and challenges of engineering stem cell therapies for clinical translation.
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Affiliation(s)
- Jun Fang
- Department of Bioengineering, Department of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200240, China.
| | - Jennifer J Li
- Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; Department of Medicine, Cardiovascular Research Institute and Institute for Regeneration Medicine, University of California, San Francisco, CA 94143, USA
| | - Xintong Zhong
- School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yue Zhou
- School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Randall J Lee
- Department of Medicine, Cardiovascular Research Institute and Institute for Regeneration Medicine, University of California, San Francisco, CA 94143, USA
| | - Ke Cheng
- Department of Biomedical Engineering, North Carolina State University, NC, USA
| | - Song Li
- Department of Bioengineering, Department of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA; Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, California 90095, USA.
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14
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Zhang L, Ma XJN, Fei YY, Han HT, Xu J, Cheng L, Li X. Stem cell therapy in liver regeneration: Focus on mesenchymal stem cells and induced pluripotent stem cells. Pharmacol Ther 2022; 232:108004. [PMID: 34597754 DOI: 10.1016/j.pharmthera.2021.108004] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/11/2021] [Accepted: 09/23/2021] [Indexed: 02/07/2023]
Abstract
The liver has the ability to repair itself after injury; however, a variety of pathological changes in the liver can affect its ability to regenerate, and this could lead to liver failure. Mesenchymal stem cells (MSCs) are considered a good source of cells for regenerative medicine, as they regulate liver regeneration through different mechanisms, and their efficacy has been demonstrated by many animal experiments and clinical studies. Induced pluripotent stem cells, another good source of MSCs, have also made great progress in the establishment of organoids, such as liver disease models, and in drug screening. Owing to the recent developments in MSCs and induced pluripotent stem cells, combined with emerging technologies including graphene, nano-biomaterials, and gene editing, precision medicine and individualized clinical treatment may be realized in the near future.
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Affiliation(s)
- Lu Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China; The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Xiao-Jing-Nan Ma
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Yuan-Yuan Fei
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China
| | - Heng-Tong Han
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Jun Xu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Lu Cheng
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China
| | - Xun Li
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China; Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou 730000, PR China; The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China.
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15
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Wang G, Heimendinger P, Ramelmeier RA, Wang W. Pluripotent stem cell-based cell therapies: current applications and future prospects. CURRENT OPINION IN BIOMEDICAL ENGINEERING 2022. [DOI: 10.1016/j.cobme.2022.100390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Wruck W, Graffmann N, Spitzhorn LS, Adjaye J. Human Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Acquire Rejuvenation and Reduced Heterogeneity. Front Cell Dev Biol 2021; 9:717772. [PMID: 34604216 PMCID: PMC8481886 DOI: 10.3389/fcell.2021.717772] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/17/2021] [Indexed: 12/20/2022] Open
Abstract
Despite the uniform selection criteria for the isolation of human mesenchymal stem cells (MSCs), considerable heterogeneity exists which reflects the distinct tissue origins and differences between individuals with respect to their genetic background and age. This heterogeneity is manifested by the variabilities seen in the transcriptomes, proteomes, secretomes, and epigenomes of tissue-specific MSCs. Here, we review literature on different aspects of MSC heterogeneity including the role of epigenetics and the impact of MSC heterogeneity on therapies. We then combine this with a meta-analysis of transcriptome data from distinct MSC subpopulations derived from bone marrow, adipose tissue, cruciate, tonsil, kidney, umbilical cord, fetus, and induced pluripotent stem cells derived MSCs (iMSCs). Beyond that, we investigate transcriptome differences between tissue-specific MSCs and pluripotent stem cells. Our meta-analysis of numerous MSC-related data sets revealed markers and associated biological processes characterizing the heterogeneity and the common features of MSCs from various tissues. We found that this heterogeneity is mainly related to the origin of the MSCs and infer that microenvironment and epigenetics are key drivers. The epigenomes of MSCs alter with age and this has a profound impact on their differentiation capabilities. Epigenetic modifications of MSCs are propagated during cell divisions and manifest in differentiated cells, thus contributing to diseased or healthy phenotypes of the respective tissue. An approach used to reduce heterogeneity caused by age- and tissue-related epigenetic and microenvironmental patterns is the iMSC concept: iMSCs are MSCs generated from induced pluripotent stem cells (iPSCs). During iMSC generation epigenetic and chromatin remodeling result in a gene expression pattern associated with rejuvenation thus allowing to overcome age-related shortcomings (e.g., limited differentiation and proliferation capacity). The importance of the iMSC concept is underlined by multiple clinical trials. In conclusion, we propose the use of rejuvenated iMSCs to bypass tissue- and age-related heterogeneity which are associated with native MSCs.
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Affiliation(s)
- Wasco Wruck
- Medical Faculty, Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Nina Graffmann
- Medical Faculty, Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Lucas-Sebastian Spitzhorn
- Medical Faculty, Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - James Adjaye
- Medical Faculty, Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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Goals and Challenges of Stem Cell-Based Therapy for Corneal Blindness Due to Limbal Deficiency. Pharmaceutics 2021; 13:pharmaceutics13091483. [PMID: 34575560 PMCID: PMC8466237 DOI: 10.3390/pharmaceutics13091483] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/09/2021] [Accepted: 09/13/2021] [Indexed: 12/13/2022] Open
Abstract
Corneal failure is a highly prevalent cause of blindness. One special cause of corneal failure occurs due to malfunction or destruction of the limbal stem cell niche, upon which the superficial cornea depends for homeostatic maintenance and wound healing. Failure of the limbal niche is referred to as limbal stem cell deficiency. As the corneal epithelial stem cell niche is easily accessible, limbal stem cell-based therapy and regenerative medicine applied to the ocular surface are among the most highly advanced forms of this novel approach to disease therapy. However, the challenges are still great, including the development of cell-based products and understanding how they work in the patient's eye. Advances are being made at the molecular, cellular, and tissue levels to alter disease processes and to reduce or eliminate blindness. Efforts must be coordinated from the most basic research to the most clinically oriented projects so that cell-based therapies can become an integrated part of the therapeutic armamentarium to fight corneal blindness. We undoubtedly are progressing along the right path because cell-based therapy for eye diseases is one of the most successful examples of global regenerative medicine.
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18
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Yamamoto R, Kino-Oka M. Design of suspension culture system with bubble sparging for human induced pluripotent stem cells in a plastic fluid. J Biosci Bioeng 2021; 132:190-197. [PMID: 34052116 DOI: 10.1016/j.jbiosc.2021.04.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 04/19/2021] [Accepted: 04/22/2021] [Indexed: 11/29/2022]
Abstract
Bubble sparging has been used to supply oxygen to large-scale bioreactor systems. However, sparged bubbles cause cell death by rupturing due to shear stress, and the foam layer carries a risk of contamination. Large-scale culture of human induced pluripotent stem cells (hiPSCs) is required for manufacturing, but hiPSCs show high sensitivity to shear stress, and also, aseptic processing is important for their expansion. In this study, a culture system with bubble sparging for hiPSC proliferation was designed using a plastic fluid as a culture medium. The rising bubble velocity in the plastic fluid decreased and was lower than that in a Newtonian fluid when the time interval between bubbles generation, Δt, was greater than 0.14 s. Under this condition, aggregate distribution in the plastic fluid was maintained without liquid flow. Although large aeration induced aggregate coalescence and growth inhibition, the apparent specific growth rate at Δt > 0.14 s increased with an increase in the aeration rate, and the maximum value was similar to that of the conventional suspension culture in a stirred bioreactor system. The gas hold-up in the plastic fluid was higher than that in a Newtonian fluid because of the lower rising bubble velocity, which leads to the suppression of bubble sparging. Therefore, our results indicated that using a plastic fluid leads to a more efficient oxygen supply without agitation in a spatial-temporal phase-transition culture system.
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Affiliation(s)
- Riku Yamamoto
- Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Masahiro Kino-Oka
- Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
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19
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Abstract
Improved stem cell-derived pancreatic islet (SC-islet) differentiation protocols robustly generate insulin-secreting β cells from patient induced pluripotent stem cells (iPSCs). These advances are enabling in vitro disease modeling studies and the development of an autologous diabetes cell replacement therapy. SC-islet technology elucidates key features of human pancreas development and diabetes disease progression through the generation of pancreatic progenitors, endocrine progenitors, and β cells derived from diabetic and nondiabetic iPSCs. Combining disease modeling with gene editing and next-generation sequencing reveals the impact of diabetes-causing mutations and diabetic phenotypes on multiple islet cell types. In addition, the supply of SC-islets, containing β and other islet cell types, is unlimited, presenting an opportunity for personalized medicine and overcoming several disadvantages posed by donor islets. This review highlights relevant studies involving iPSC-β cells and progenitors, encompassing new conclusions involving cells from patients with diabetes and the therapeutic potential of iPSC-β cells.
Improved differentiation protocols generate pancreatic islet from patient stem cells Diabetic stem cell-derived islet studies identified key markers for cell function Gene editing aims to address unmet needs for stem cell therapy field Stem cell-derived islets are a promising source for diabetes stem cell therapy
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Spellicy SE, Hess DC. The Immunomodulatory Capacity of Induced Pluripotent Stem Cells in the Post-stroke Environment. Front Cell Dev Biol 2021; 9:647415. [PMID: 33796535 PMCID: PMC8007866 DOI: 10.3389/fcell.2021.647415] [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: 12/29/2020] [Accepted: 02/25/2021] [Indexed: 11/13/2022] Open
Abstract
Inflammation has proven to be a key contributing factor to the pathogenesis of ischemic and hemorrhagic stroke. This sequential and progressive response, marked by proliferation of resident immune cells and recruitment of peripheral immune populations, results in increased oxidative stress, and neuronal cell death. Therapeutics aimed at quelling various stages of this post-stroke inflammatory response have shown promise recently, one of which being differentiated induced pluripotent stem cells (iPSCs). While direct repopulation of damaged tissues and enhanced neurogenesis are hypothesized to encompass some of the therapeutic potential of iPSCs, recent evidence has demonstrated a substantial paracrine effect on neuroinflammation. Specifically, investigation of iPSCs, iPSC-neural progenitor cells (iPSC-NPCs), and iPSC-neuroepithelial like stem cells (iPSC-lt-NESC) has demonstrated significant immunomodulation of proinflammatory signaling and endogenous inflammatory cell populations, such as microglia. This review aims to examine the mechanisms by which iPSCs mediate neuroinflammation in the post-stroke environment, as well as delineate avenues for further investigation.
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Affiliation(s)
- Samantha E Spellicy
- MD-Ph.D. Program, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - David C Hess
- Dean's Office, Medical College of Georgia at Augusta University, Augusta, GA, United States
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21
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Bourgeois S, Sawatani T, Van Mulders A, De Leu N, Heremans Y, Heimberg H, Cnop M, Staels W. Towards a Functional Cure for Diabetes Using Stem Cell-Derived Beta Cells: Are We There Yet? Cells 2021; 10:cells10010191. [PMID: 33477961 PMCID: PMC7835995 DOI: 10.3390/cells10010191] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/12/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus is a pandemic metabolic disorder that results from either the autoimmune destruction or the dysfunction of insulin-producing pancreatic beta cells. A promising cure is beta cell replacement through the transplantation of islets of Langerhans. However, donor shortage hinders the widespread implementation of this therapy. Human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells, represent an attractive alternative beta cell source for transplantation. Although major advances over the past two decades have led to the generation of stem cell-derived beta-like cells that share many features with genuine beta cells, producing fully mature beta cells remains challenging. Here, we review the current status of beta cell differentiation protocols and highlight specific challenges that are associated with producing mature beta cells. We address the challenges and opportunities that are offered by monogenic forms of diabetes. Finally, we discuss the remaining hurdles for clinical application of stem cell-derived beta cells and the status of ongoing clinical trials.
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Affiliation(s)
- Stephanie Bourgeois
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; (S.B.); (A.V.M.); (N.D.L.); (Y.H.); (H.H.)
| | - Toshiaki Sawatani
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, 1070 Brussels, Belgium; (T.S.); (M.C.)
| | - Annelore Van Mulders
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; (S.B.); (A.V.M.); (N.D.L.); (Y.H.); (H.H.)
| | - Nico De Leu
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; (S.B.); (A.V.M.); (N.D.L.); (Y.H.); (H.H.)
- Department of Endocrinology, University Hospital Brussels, 1090 Brussels, Belgium
- Department of Endocrinology, ASZ Aalst, 9300 Aalst, Belgium
| | - Yves Heremans
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; (S.B.); (A.V.M.); (N.D.L.); (Y.H.); (H.H.)
| | - Harry Heimberg
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; (S.B.); (A.V.M.); (N.D.L.); (Y.H.); (H.H.)
| | - Miriam Cnop
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, 1070 Brussels, Belgium; (T.S.); (M.C.)
- Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium
| | - Willem Staels
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; (S.B.); (A.V.M.); (N.D.L.); (Y.H.); (H.H.)
- Service of Pediatric Endocrinology, Department of Pediatrics, KidZ Health Castle, Universitair Ziekenhuis Brussel (UZ Brussel), 1090 Brussels, Belgium
- Correspondence: ; Tel.: +32-0-24774473
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22
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Ortiz-Cordero C, Azzag K, Perlingeiro RCR. Fukutin-Related Protein: From Pathology to Treatments. Trends Cell Biol 2020; 31:197-210. [PMID: 33272829 DOI: 10.1016/j.tcb.2020.11.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 11/02/2020] [Accepted: 11/04/2020] [Indexed: 12/27/2022]
Abstract
Fukutin-related protein (FKRP) is a glycosyltransferase involved in the functional glycosylation of α-dystroglycan (DG), a key component in the link between the cytoskeleton and the extracellular matrix (ECM). Mutations in FKRP lead to dystroglycanopathies with broad severity, including limb-girdle and congenital muscular dystrophy. Studies over the past 5 years have elucidated the function of FKRP, which has expanded the number of therapeutic opportunities for patients carrying FKRP mutations. These include small molecules, gene delivery, and cell therapy. Here we summarize recent findings on the function of FKRP and describe available models for studying diseases and testing therapeutics. Lastly, we highlight preclinical studies that hold potential for the treatment of FKRP-associated dystroglycanopathies.
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Affiliation(s)
- Carolina Ortiz-Cordero
- Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, MN, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA
| | - Karim Azzag
- Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Rita C R Perlingeiro
- Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, MN, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.
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23
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Flahou C, Sugimoto N, Eto K. [Novel platelet pharming using human induced pluripotent stem cells]. BULLETIN DE L ACADEMIE NATIONALE DE MEDECINE 2020; 204:961-970. [PMID: 33012790 PMCID: PMC7521593 DOI: 10.1016/j.banm.2020.09.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 09/08/2020] [Indexed: 11/14/2022]
Abstract
La production in vitro de plaquettes offre une opportunité de résoudre les problèmes liés aux limitations d’approvisionnement et à la sécurité des dons de produits dérivés du sang. Les cellules souches pluripotentes induites – ou iPSC – sont une source idéale pour la production de cellules à des fins de thérapies régénératives. Nous avons précédemment établi avec succès une lignée mégacaryocytaire immortalisée à partir d’iPSC. Celle-ci possède une capacité de prolifération fiable. Par ailleurs, il est possible de les cryoconserver. Elle est donc une source adaptée de cellules primaires pour la production de plaquettes suivant les Bonnes Pratiques de Fabrication (BPF). Dans le même temps, la capacité améliorée des bioréacteurs à reproduire certaines conditions physiologiques, telle que la turbulence, de pair avec la découverte de molécules favorisant la thrombopoïèse, a contribué à l’accomplissement de la production de plaquettes en quantité et qualité suffisantes pour répondre aux besoins cliniques. La production de plaquettes à partir de cellules iPS s’étend aussi aux patients en état de réfraction allo-immune, par la production de plaquettes autologues ou dont on a génétiquement manipulé l’expression des Antigènes des Leucocytes Humains (HLA) et des Antigènes Plaquettaires Humain (HPA). Considérant ces avancées fondamentales, les plaquettes iPSC avec expression des HLA modifiées se présentent comme un potentiel produit de transfusion universel. Dans cette revue, nous souhaitons apporter une vue d’ensemble de la production in vitro de plaquettes à partir de cellules iPS, et de son possible potentiel transformatif, d’importance capitale dans le domaine de la transfusion des produits sanguins.
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Affiliation(s)
- C Flahou
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, 53, Kawahara-cho, 606-8507 Shogoin, Sakyo-ku, Kyoto, Japon
| | - N Sugimoto
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, 53, Kawahara-cho, 606-8507 Shogoin, Sakyo-ku, Kyoto, Japon
| | - K Eto
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, 53, Kawahara-cho, 606-8507 Shogoin, Sakyo-ku, Kyoto, Japon.,Department of Regenerative Medicine, Chiba University Graduate School of Medicine, Chiba, Japon
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24
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Hu X, Kueppers ST, Kooreman NG, Gravina A, Wang D, Tediashvili G, Schlickeiser S, Frentsch M, Nikolaou C, Thiel A, Marcus S, Fuchs S, Velden J, Reichenspurner H, Volk HD, Deuse T, Schrepfer S. The H-Y Antigen in Embryonic Stem Cells Causes Rejection in Syngeneic Female Recipients. Stem Cells Dev 2020; 29:1179-1189. [PMID: 32723003 DOI: 10.1089/scd.2019.0299] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Pluripotent stem cells are promising candidates for cell-based regenerative therapies. To avoid rejection of transplanted cells, several approaches are being pursued to reduce immunogenicity of the cells or modulate the recipient's immune response. These include gene editing to reduce the antigenicity of cell products, immunosuppression of the host, or using major histocompatibility complex-matched cells from cell banks. In this context, we have investigated the antigenicity of H-Y antigens, a class of minor histocompatibility antigens encoded by the Y chromosome, to assess whether the gender of the donor affects the cell's antigenicity. In a murine transplant model, we show that the H-Y antigen in undifferentiated embryonic stem cells (ESCs), as well as ESC-derived endothelial cells, provokes T- and B cell responses in female recipients.
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Affiliation(s)
- Xiaomeng Hu
- Transplant and Stem Cell Immunobiology Lab, Department of Surgery, University of California, San Francisco, California, USA.,Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany.,University Heart & Vascular Center Hamburg, Hamburg, Germany
| | - Simon T Kueppers
- Transplant and Stem Cell Immunobiology Lab, Department of Surgery, University of California, San Francisco, California, USA.,Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany.,University Heart & Vascular Center Hamburg, Hamburg, Germany
| | - Nigel G Kooreman
- Stanford Cardiovascular Institute, Stanford University, Stanford, California, USA.,Department of Medicine, Stanford University, Stanford, California, USA.,Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA.,Department of Vascular Surgery, Leiden University Medical Center, Leiden, the Netherlands
| | - Alessia Gravina
- Transplant and Stem Cell Immunobiology Lab, Department of Surgery, University of California, San Francisco, California, USA.,Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany
| | - Dong Wang
- Transplant and Stem Cell Immunobiology Lab, Department of Surgery, University of California, San Francisco, California, USA.,Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany.,University Heart & Vascular Center Hamburg, Hamburg, Germany
| | - Grigol Tediashvili
- Transplant and Stem Cell Immunobiology Lab, Department of Surgery, University of California, San Francisco, California, USA.,Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany.,University Heart & Vascular Center Hamburg, Hamburg, Germany
| | - Stephan Schlickeiser
- BIH-Center for Regenerative Therapies (BCRT), Charité University Medicine and Berlin Institute of Health (BIH), Berlin, Germany.,Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, BIH, Berlin, Germany
| | - Marco Frentsch
- BIH-Center for Regenerative Therapies (BCRT), Charité University Medicine and Berlin Institute of Health (BIH), Berlin, Germany
| | - Christos Nikolaou
- BIH-Center for Regenerative Therapies (BCRT), Charité University Medicine and Berlin Institute of Health (BIH), Berlin, Germany
| | - Andreas Thiel
- BIH-Center for Regenerative Therapies (BCRT), Charité University Medicine and Berlin Institute of Health (BIH), Berlin, Germany
| | - Sivan Marcus
- Transplant and Stem Cell Immunobiology Lab, Department of Surgery, University of California, San Francisco, California, USA
| | - Sigrid Fuchs
- Institute of Human Genetics, University Medical Center Hamburg, Hamburg, Germany
| | - Joachim Velden
- Evotec AG, Histopathology and In Vivo Pharmacology, Hamburg, Germany
| | - Hermann Reichenspurner
- Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany.,University Heart & Vascular Center Hamburg, Hamburg, Germany
| | - Hans-Dieter Volk
- BIH-Center for Regenerative Therapies (BCRT), Charité University Medicine and Berlin Institute of Health (BIH), Berlin, Germany.,Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, BIH, Berlin, Germany
| | - Tobias Deuse
- Transplant and Stem Cell Immunobiology Lab, Department of Surgery, University of California, San Francisco, California, USA
| | - Sonja Schrepfer
- Transplant and Stem Cell Immunobiology Lab, Department of Surgery, University of California, San Francisco, California, USA.,Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany.,University Heart & Vascular Center Hamburg, Hamburg, Germany
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25
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Suda S, Nito C, Yokobori S, Sakamoto Y, Nakajima M, Sowa K, Obinata H, Sasaki K, Savitz SI, Kimura K. Recent Advances in Cell-Based Therapies for Ischemic Stroke. Int J Mol Sci 2020; 21:ijms21186718. [PMID: 32937754 PMCID: PMC7555943 DOI: 10.3390/ijms21186718] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/09/2020] [Accepted: 09/10/2020] [Indexed: 12/14/2022] Open
Abstract
Stroke is the most prevalent cardiovascular disease worldwide, and is still one of the leading causes of death and disability. Stem cell-based therapy is actively being investigated as a new potential treatment for certain neurological disorders, including stroke. Various types of cells, including bone marrow mononuclear cells, bone marrow mesenchymal stem cells, dental pulp stem cells, neural stem cells, inducible pluripotent stem cells, and genetically modified stem cells have been found to improve neurological outcomes in animal models of stroke, and there are some ongoing clinical trials assessing their efficacy in humans. In this review, we aim to summarize the recent advances in cell-based therapies to treat stroke.
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Affiliation(s)
- Satoshi Suda
- Department of Neurology, Nippon Medical School, Tokyo 113-8602, Japan; (C.N.); (Y.S.); (M.N.); (K.S.); (K.K.)
- Correspondence: ; Tel.: +81-3-3822-2131; Fax: +81-3-3822-4865
| | - Chikako Nito
- Department of Neurology, Nippon Medical School, Tokyo 113-8602, Japan; (C.N.); (Y.S.); (M.N.); (K.S.); (K.K.)
| | - Shoji Yokobori
- Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8602, Japan; (S.Y.); (H.O.); (K.S.)
| | - Yuki Sakamoto
- Department of Neurology, Nippon Medical School, Tokyo 113-8602, Japan; (C.N.); (Y.S.); (M.N.); (K.S.); (K.K.)
| | - Masataka Nakajima
- Department of Neurology, Nippon Medical School, Tokyo 113-8602, Japan; (C.N.); (Y.S.); (M.N.); (K.S.); (K.K.)
| | - Kota Sowa
- Department of Neurology, Nippon Medical School, Tokyo 113-8602, Japan; (C.N.); (Y.S.); (M.N.); (K.S.); (K.K.)
| | - Hirofumi Obinata
- Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8602, Japan; (S.Y.); (H.O.); (K.S.)
| | - Kazuma Sasaki
- Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8602, Japan; (S.Y.); (H.O.); (K.S.)
| | - Sean I. Savitz
- Institute for Stroke and Cerebrovascular Disease, UTHealth, Houston, TX 77030, USA;
| | - Kazumi Kimura
- Department of Neurology, Nippon Medical School, Tokyo 113-8602, Japan; (C.N.); (Y.S.); (M.N.); (K.S.); (K.K.)
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26
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Selvaraj S, Kyba M, Perlingeiro RCR. Pluripotent Stem Cell-Based Therapeutics for Muscular Dystrophies. Trends Mol Med 2020; 25:803-816. [PMID: 31473142 DOI: 10.1016/j.molmed.2019.07.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 06/30/2019] [Accepted: 07/08/2019] [Indexed: 02/06/2023]
Abstract
Pluripotent stem cells (PSCs) represent an attractive cell source for treating muscular dystrophies (MDs) since they easily allow for the generation of large numbers of highly regenerative myogenic progenitors. Using reprogramming technology, patient-specific PSCs have been derived for several types of MDs, and genome editing has allowed correction of mutations, opening the opportunity for their therapeutic application in an autologous transplantation setting. However, there has been limited progress on preclinical studies that validate the therapeutic potential of these gene corrected PSC-derived myogenic progenitors. In this review, we highlight the major research advances, challenges, and future prospects towards the development of PSC-based therapeutics for MDs.
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Affiliation(s)
- Sridhar Selvaraj
- Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Michael Kyba
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA
| | - Rita C R Perlingeiro
- Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, MN, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.
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27
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Yoon SY, Yoon JA, Park M, Shin EY, Jung S, Lee JE, Eum JH, Song H, Lee DR, Lee WS, Lyu SW. Recovery of ovarian function by human embryonic stem cell-derived mesenchymal stem cells in cisplatin-induced premature ovarian failure in mice. Stem Cell Res Ther 2020; 11:255. [PMID: 32586410 PMCID: PMC7318510 DOI: 10.1186/s13287-020-01769-6] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 05/07/2020] [Accepted: 06/11/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Clinical use of mesenchymal stem cells (MSCs) requires a uniform cell population, and their harvesting is invasive and produces a limited number of cells. Human embryonic stem cell-derived MSCs (hESC-MSCs) can differentiate into three germ layers and possess immunosuppressive effects in vitro. Anticancer treatment is a well-known risk factor for premature ovarian failure (POF). In this study, we investigated the effect of hESC-MSC on recovery of ovarian function in cisplatin-induced POF in mice. METHODS Female mice received intraperitoneal cisplatin for 10 days. On day 12, CHA15-derived hESC-MSCs were transplanted into the mice by tail vein injection. An injection of PBS served as the negative control. Ovaries were removed 28 days after transplantation for assessment of ovarian histology, immunostaining, and fertility testing by superovulation and in vitro fertilization. hESC-MSC transplantation into mice with cisplatin-induced damage restored body weight and ovary size. RESULTS Mean primary and primordial follicle counts in the hESC-MSC group were significantly improved compared to the PBS group (P < 0.05), and counts of zona pellucida remnants, an apoptotic sign in ovarian follicles, were significantly reduced (P < 0.05). TUNEL assays and cleaved PARP immunostaining indicated apoptosis, which led to loss of ovarian stromal cells in negative control mice, while Ki-67 was higher in the hESC-MSC group and in non-cisplatin-treated controls than in the PBS group. Ovulation was reduced in the PBS group but recovered significantly in the hESC-MSC group. Rates of blastocyst formation from ovulated eggs and live births per mouse also recovered significantly in the hESC-MSC group. CONCLUSIONS hESC-MSC restored structure and function in the cisplatin-damaged ovary. Our study provides new insights into the great clinical potential of human hESC-MSC in treating POF.
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Affiliation(s)
- Sook Young Yoon
- Fertility Center of CHA Gangnam Medical Center, CHA University, 569 Nonhyun-ro, Gangnam-Gu, Seoul, 06125, South Korea
| | - Jung Ah Yoon
- Fertility Center of CHA Gangnam Medical Center, CHA University, 569 Nonhyun-ro, Gangnam-Gu, Seoul, 06125, South Korea
| | - Mira Park
- Department of Biomedical Science, CHA University, Seongnam-si, South Korea
| | - Eun-Young Shin
- Department of Biomedical Science, CHA University, Seongnam-si, South Korea
| | - Sookyung Jung
- CHA Advanced Research Institute, Seongnam-si, South Korea
| | - Jeoung Eun Lee
- CHA Advanced Research Institute, Seongnam-si, South Korea
| | - Jin Hee Eum
- Fertility Center of CHA Gangnam Medical Center, CHA University, 569 Nonhyun-ro, Gangnam-Gu, Seoul, 06125, South Korea
| | - Haengseok Song
- Department of Biomedical Science, CHA University, Seongnam-si, South Korea
| | - Dong Ryul Lee
- CHA Advanced Research Institute, Seongnam-si, South Korea.,Department of Biomedical Science, CHA University, Seongnam-si, South Korea
| | - Woo Sik Lee
- Fertility Center of CHA Gangnam Medical Center, CHA University, 569 Nonhyun-ro, Gangnam-Gu, Seoul, 06125, South Korea
| | - Sang Woo Lyu
- Fertility Center of CHA Gangnam Medical Center, CHA University, 569 Nonhyun-ro, Gangnam-Gu, Seoul, 06125, South Korea.
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28
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Yoshihara M, Oguchi A, Murakawa Y. Genomic Instability of iPSCs and Challenges in Their Clinical Applications. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1201:23-47. [PMID: 31898780 DOI: 10.1007/978-3-030-31206-0_2] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Generation of human-induced pluripotent stem cells (iPSCs) from somatic cells has opened the possibility to design novel therapeutic approaches. In 2014, the first-in-human clinical trial of iPSC-based therapy was conducted. However, the transplantation for the second patient was discontinued at least in part due to genetic aberrations detected in iPSCs. Moreover, many studies have reported genetic aberrations in iPSCs with the rapid progress in genomic technologies. The presence of genomic instability raises serious safety concerns and can hamper the advancement of iPSC-based therapies. Here, we summarize our current knowledge on genomic instability of iPSCs and challenges in their clinical applications. In view of the recent expansion of stem cell therapies, it is crucial to gain deeper mechanistic insights into the genetic aberrations, ranging from chromosomal aberrations, copy number variations to point mutations. On the basis of their origin, these genetic aberrations in iPSCs can be classified as (i) preexisting mutations in parental somatic cells, (ii) reprogramming-induced mutations, and (iii) mutations that arise during in vitro culture. However, it is still unknown whether these genetic aberrations in iPSCs can be an actual risk factor for adverse effects. Intersection of the genomic data on iPSCs with the patients' clinical follow-up data will help to produce evidence-based criteria for clinical application. Furthermore, we discuss novel approaches to generate iPSCs with fewer genetic aberrations. Better understanding of iPSCs from both basic and clinical aspects will pave the way for iPSC-based therapies.
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Affiliation(s)
- Masahito Yoshihara
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Akiko Oguchi
- RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
| | - Yasuhiro Murakawa
- RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
- IFOM, The FIRC Institute of Molecular Oncology, Milan, Italy.
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29
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Targeting cell plasticity for regeneration: From in vitro to in vivo reprogramming. Adv Drug Deliv Rev 2020; 161-162:124-144. [PMID: 32822682 DOI: 10.1016/j.addr.2020.08.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 08/13/2020] [Accepted: 08/14/2020] [Indexed: 12/14/2022]
Abstract
The discovery of induced pluripotent stem cells (iPSCs), reprogrammed to pluripotency from somatic cells, has transformed the landscape of regenerative medicine, disease modelling and drug discovery pipelines. Since the first generation of iPSCs in 2006, there has been enormous effort to develop new methods that increase reprogramming efficiency, and obviate the need for viral vectors. In parallel to this, the promise of in vivo reprogramming to convert cells into a desired cell type to repair damage in the body, constitutes a new paradigm in approaches for tissue regeneration. This review article explores the current state of reprogramming techniques for iPSC generation with a specific focus on alternative methods that use biophysical and biochemical stimuli to reduce or eliminate exogenous factors, thereby overcoming the epigenetic barrier towards vector-free approaches with improved clinical viability. We then focus on application of iPSC for therapeutic approaches, by giving an overview of ongoing clinical trials using iPSCs for a variety of health conditions and discuss future scope for using materials and reagents to reprogram cells in the body.
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30
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Ortuño-Costela MDC, Cerrada V, García-López M, Gallardo ME. The Challenge of Bringing iPSCs to the Patient. Int J Mol Sci 2019; 20:E6305. [PMID: 31847153 PMCID: PMC6940848 DOI: 10.3390/ijms20246305] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 12/10/2019] [Accepted: 12/11/2019] [Indexed: 12/13/2022] Open
Abstract
The implementation of induced pluripotent stem cells (iPSCs) in biomedical research more than a decade ago, resulted in a huge leap forward in the highly promising area of personalized medicine. Nowadays, we are even closer to the patient than ever. To date, there are multiple examples of iPSCs applications in clinical trials and drug screening. However, there are still many obstacles to overcome. In this review, we will focus our attention on the advantages of implementing induced pluripotent stem cells technology into the clinics but also commenting on all the current drawbacks that could hinder this promising path towards the patient.
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Affiliation(s)
- María del Carmen Ortuño-Costela
- Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain. Instituto de Investigaciones Biomédicas “Alberto Sols”, (UAM-CSIC), 28029 Madrid, Spain;
- Grupo de Investigación Traslacional con células iPS, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), 28041 Madrid, Spain; (V.C.); (M.G.-L.)
| | - Victoria Cerrada
- Grupo de Investigación Traslacional con células iPS, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), 28041 Madrid, Spain; (V.C.); (M.G.-L.)
| | - Marta García-López
- Grupo de Investigación Traslacional con células iPS, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), 28041 Madrid, Spain; (V.C.); (M.G.-L.)
| | - M. Esther Gallardo
- Grupo de Investigación Traslacional con células iPS, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), 28041 Madrid, Spain; (V.C.); (M.G.-L.)
- Centro de Investigación Biomédica en Red (CIBERER), 28029 Madrid, Spain
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31
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Vitillo L, Tovell VE, Coffey P. Treatment of Age-Related Macular Degeneration with Pluripotent Stem Cell-Derived Retinal Pigment Epithelium. Curr Eye Res 2019; 45:361-371. [DOI: 10.1080/02713683.2019.1691237] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Loriana Vitillo
- The London Project to Cure Blindness, Institute of Ophthalmology, University College London (UCL), London, UK
| | - Victoria E. Tovell
- The London Project to Cure Blindness, Institute of Ophthalmology, University College London (UCL), London, UK
| | - Pete Coffey
- The London Project to Cure Blindness, Institute of Ophthalmology, University College London (UCL), London, UK
- Center for Stem Cell Biology and Engineering, University of California Santa Barbara, Santa Barbara, CA, USA
- NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, UCL Institute of Ophthalmology, London, UK
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32
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Ben M’Barek K, Habeler W, Regent F, Monville C. Developing Cell-Based Therapies for RPE-Associated Degenerative Eye Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1186:55-97. [DOI: 10.1007/978-3-030-28471-8_3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Steichen C, Hannoun Z, Luce E, Hauet T, Dubart-Kupperschmitt A. Genomic integrity of human induced pluripotent stem cells: Reprogramming, differentiation and applications. World J Stem Cells 2019; 11:729-747. [PMID: 31692979 PMCID: PMC6828592 DOI: 10.4252/wjsc.v11.i10.729] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 06/13/2019] [Accepted: 07/30/2019] [Indexed: 02/06/2023] Open
Abstract
Ten years after the initial generation of induced pluripotent stem cells (hiPSCs) from human tissues, their potential is no longer questioned, with over 15000 publications listed on PubMed, covering various fields of research; including disease modeling, cell therapy strategies, pharmacology/toxicology screening and 3D organoid systems. However, despite evidences that the presence of mutations in hiPSCs should be a concern, publications addressing genomic integrity of these cells represent less than 1% of the literature. After a first overview of the mutation types currently reported in hiPSCs, including karyotype abnormalities, copy number variations, single point mutation as well as uniparental disomy, this review will discuss the impact of reprogramming parameters such as starting cell type and reprogramming method on the maintenance of the cellular genomic integrity. Then, a specific focus will be placed on culture conditions and subsequent differentiation protocols and how their may also trigger genomic aberrations within the cell population of interest. Finally, in a last section, the impact of genomic alterations on the possible usages of hiPSCs and their derivatives will also be exemplified and discussed. We will also discuss which techniques or combination of techniques should be used to screen for genomic abnormalities with a particular focus on the necessary quality controls and the potential alternatives.
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Affiliation(s)
- Clara Steichen
- INSERM U1082 IRTOMIT, CHU de Poitiers, Poitiers F-86021, France
- Université de Poitiers, Faculté de Médecine et Pharmacie, Bâtiment D1, 6 rue de la milétrie, TSA 51115, 86073 Poitiers Cedex 9, France
| | - Zara Hannoun
- INSERM U1193, Hôpital Paul Brousse, Villejuif F-94800, France
- UMR_S1193, Université Paris-Saclay, Hôpital Paul Brousse, Villejuif F-94800, France
- The Jenner Institute, University of Oxford, Oxford OX3 7DQ, United Kingdom
| | - Eléanor Luce
- INSERM U1193, Hôpital Paul Brousse, Villejuif F-94800, France
- UMR_S1193, Université Paris-Saclay, Hôpital Paul Brousse, Villejuif F-94800, France
- Département Hospitalo-Universitaire Hepatinov, Hôpital Paul Brousse, Villejuif F-94807, France
| | - Thierry Hauet
- INSERM U1082 IRTOMIT, CHU de Poitiers, Poitiers F-86021, France
- Université de Poitiers, Faculté de Médecine et Pharmacie, Bâtiment D1, 6 rue de la milétrie, TSA 51115, 86073 Poitiers Cedex 9, France
- Service de Biochimie, Pôle Biospharm, CHU de Poitiers, Poitiers F-86021, France
- Fédération Hospitalo-Universitaire SUPORT, CHU de Poitiers, Poitiers F-86021, France
| | - Anne Dubart-Kupperschmitt
- INSERM U1193, Hôpital Paul Brousse, Villejuif F-94800, France
- UMR_S1193, Université Paris-Saclay, Hôpital Paul Brousse, Villejuif F-94800, France
- Département Hospitalo-Universitaire Hepatinov, Hôpital Paul Brousse, Villejuif F-94807, France
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Enrich E, Campos E, Martorell L, Herrero MJ, Vidal F, Querol S, Rudilla F. HLA-A, -B, -C, -DRB1, and -DQB1 allele and haplotype frequencies: An analysis of umbilical cord blood units at the Barcelona Cord Blood Bank. HLA 2019; 94:347-359. [PMID: 31353832 DOI: 10.1111/tan.13644] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 07/18/2019] [Accepted: 07/25/2019] [Indexed: 12/16/2022]
Abstract
Allele-level HLA compatibility in cord blood transplantation has been associated with better transplant outcomes and is recommended as a selection criterion. It is also a crucial aspect for other therapeutic applications involving cord blood-derived cells. Determination of high-resolution HLA frequencies is an important step towards improving the quality of cord blood banks. We analyzed HLA-A, -B, -C, -DRB1, and -DQB1 allele frequencies in 5458 high-quality cord blood units from the Barcelona Cord Blood Bank and identified 275 class I and 121 class II HLA alleles. A*02:01, B*44:03, C*07:01, DRB1*07:01 and DQB1*03:01 were the most frequent alleles at each locus. We detected 26 novel alleles and were able to determine the presence or absence of some null alleles, including C*04:09N, in a large number of units. We also analyzed maternal HLA typing information for 1877 units to determine real haplotype frequencies and linkage disequilibrium. A*29:02-B*44:03-C*16:01-DRB1*07:01-DQB1*02:02 was the most frequent HLA haplotype and the DRB1-DQB1 gene pair contained the two-locus haplotypes with the strongest linkage disequilibrium values. Four of the 11 unique haplotypes identified in the HLA-homozygous cord blood units were the top-ranking haplotypes identified and were present in 18% of the cohort. This is the first study to report on HLA allele and haplotype frequencies for umbilical cord blood units from the Barcelona Cord Blood Bank and the largest study to date involving two fields of HLA resolution typing of Spanish registry data.
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Affiliation(s)
- Emma Enrich
- Immunogenetics and Histocompatibility Laboratory, Banc de Sang i Teixits, Barcelona, Spain
- Transfusional Medicine Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
| | - Eva Campos
- Immunogenetics and Histocompatibility Laboratory, Banc de Sang i Teixits, Barcelona, Spain
| | - Lluís Martorell
- Congenital Coagulopathy Laboratory, Banc de Sang i Teixits, Barcelona, Spain
- Cell Therapy Unit, Banc de Sang i Teixits, Barcelona, Spain
| | - María José Herrero
- Immunogenetics and Histocompatibility Laboratory, Banc de Sang i Teixits, Barcelona, Spain
| | - Francisco Vidal
- Transfusional Medicine Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
- Congenital Coagulopathy Laboratory, Banc de Sang i Teixits, Barcelona, Spain
- CIBER of Cardiovascular Diseases (CIBERCV), Madrid, Spain
| | - Sergi Querol
- Transfusional Medicine Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
- Cell Therapy Unit, Banc de Sang i Teixits, Barcelona, Spain
| | - Francesc Rudilla
- Immunogenetics and Histocompatibility Laboratory, Banc de Sang i Teixits, Barcelona, Spain
- Transfusional Medicine Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
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Research Highlights. Transplantation 2019. [DOI: 10.1097/tp.0000000000002884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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36
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HLA concordance between hematopoietic stem cell transplantation patients and umbilical cord blood units: Implications for cord blood banking in admixed populations. Hum Immunol 2019; 80:714-722. [PMID: 31101373 DOI: 10.1016/j.humimm.2019.05.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 05/01/2019] [Accepted: 05/10/2019] [Indexed: 11/22/2022]
Abstract
Umbilical cord blood stem cell transplantation is an important choice for treating a variety of hematopoietic, neoplastic, and genetic disorders. The optimal size for a cord blood bank to provide matching units for 80% of patients requiring a stem cell transplantation procedure depends on the particular characteristics of each population. In this study, we analyzed the immunogenetic diversity of a sample set of Mexican patients suffering from blood, hematopoietic, and immunological diseases, to assess the best strategy for cord blood banking. For achieving that, we analyzed HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1 genotype and allele frequencies of both units from the bioarchive of the Umbilical Cord Blood Bank from La Raza and patients requiring a stem cell transplant and compared these variables with data from the same geographic and genetic context. We were able to detect significant differences for at least half of the alleles were observed for HLA class I and class II genes between units and patients. Five Native American haplotypes had lower frequencies in patients sample than in the cord blood units. Genetic admixture estimations for both groups showed a higher contribution of Native American component in the cord blood units. Differences in ancestral components in the Umbilical Cord Blood Bank from La Raza and six virtual banks modeled from a pool of Mexican mixed ancestry individuals show that genetic background is important in cord blood collection. In conclusion, increasing diversity over quantity of new cord blood units will improve the cost effectiveness of cord blood banking and health policies regarding hematopoietic stem cell transplantation in admixed populations such as those present in Latin American countries.
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37
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Recent Updates on Induced Pluripotent Stem Cells in Hematological Disorders. Stem Cells Int 2019; 2019:5171032. [PMID: 31191673 PMCID: PMC6525795 DOI: 10.1155/2019/5171032] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 03/31/2019] [Indexed: 02/07/2023] Open
Abstract
Over the past decade, enormous progress has been made in the field of induced pluripotent stem cells (iPSCs). Patients' somatic cells such as skin fibroblasts or blood cells can be used to generate disease-specific pluripotent stem cells, which have unlimited proliferation and can differentiate into all cell types of the body. Human iPSCs offer great promises and opportunities for treatments of degenerative diseases and studying disease pathology and drug screening. So far, many iPSC-derived disease models have led to the discovery of novel pathological mechanisms as well as new drugs in the pipeline that have been tested in the iPSC-derived cells for efficacy and potential toxicities. Furthermore, recent advances in genome editing technology in combination with the iPSC technology have provided a versatile platform for studying stem cell biology and regenerative medicine. In this review, an overview of iPSCs, patient-specific iPSCs for disease modeling and drug screening, applications of iPSCs and genome editing technology in hematological disorders, remaining challenges, and future perspectives of iPSCs in hematological diseases will be discussed.
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38
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Abstract
Polymorphic HLAs form the primary immune barrier to cell therapy. In addition, innate immune surveillance impacts cell engraftment, yet a strategy to control both, adaptive and innate immunity, is lacking. Here we employed multiplex genome editing to specifically ablate the expression of the highly polymorphic HLA-A/-B/-C and HLA class II in human pluripotent stem cells. Furthermore, to prevent innate immune rejection and further suppress adaptive immune responses, we expressed the immunomodulatory factors PD-L1, HLA-G, and the macrophage "don't-eat me" signal CD47 from the AAVS1 safe harbor locus. Utilizing in vitro and in vivo immunoassays, we found that T cell responses were blunted. Moreover, NK cell killing and macrophage engulfment of our engineered cells were minimal. Our results describe an approach that effectively targets adaptive as well as innate immune responses and may therefore enable cell therapy on a broader scale.
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39
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Yoon SY. Mesenchymal stem cells for restoration of ovarian function. Clin Exp Reprod Med 2019; 46:1-7. [PMID: 30827071 PMCID: PMC6436469 DOI: 10.5653/cerm.2019.46.1.1] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 02/08/2019] [Indexed: 12/11/2022] Open
Abstract
With the progress of regenerative medicine, mesenchymal stem cells (MSCs) have received attention as a way to restore ovarian function. It has been reported that MSCs derived from bone marrow, adipose, umbilical cord blood, menstrual blood, and amniotic fluid improved ovarian function. In light of previous studies and advances in this field, there are increased expectations regarding the utilization of MSCs to restore ovarian function. This review summarizes recent research into potential applications of MSCs in women with infertility or primary ovarian insufficiency, including cases where these conditions are induced by anticancer therapy.
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Affiliation(s)
- Sook Young Yoon
- Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, Korea
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40
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Gasparini SJ, Llonch S, Borsch O, Ader M. Transplantation of photoreceptors into the degenerative retina: Current state and future perspectives. Prog Retin Eye Res 2018; 69:1-37. [PMID: 30445193 DOI: 10.1016/j.preteyeres.2018.11.001] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 10/29/2018] [Accepted: 11/06/2018] [Indexed: 12/12/2022]
Abstract
The mammalian retina displays no intrinsic regenerative capacities, therefore retinal degenerative diseases such as age-related macular degeneration (AMD) or retinitis pigmentosa (RP) result in a permanent loss of the light-sensing photoreceptor cells. The degeneration of photoreceptors leads to vision impairment and, in later stages, complete blindness. Several therapeutic strategies have been developed to slow down or prevent further retinal degeneration, however a definitive cure i.e. replacement of the lost photoreceptors, has not yet been established. Cell-based treatment approaches, by means of photoreceptor transplantation, have been studied in pre-clinical animal models over the last three decades. The introduction of pluripotent stem cell-derived retinal organoids represents, in principle, an unlimited source for the generation of transplantable human photoreceptors. However, safety, immunological and reproducibility-related issues regarding the use of such cells still need to be solved. Moreover, the recent finding of cytoplasmic material transfer between donor and host photoreceptors demands reinterpretation of several former transplantation studies. At the same time, material transfer between healthy donor and dysfunctional patient photoreceptors also offers a potential alternative strategy for therapeutic intervention. In this review we discuss the history and current state of photoreceptor transplantation, the techniques used to assess rescue of visual function, the prerequisites for effective transplantation as well as the main roadblocks, including safety and immune response to the graft, that need to be overcome for successful clinical translation of photoreceptor transplantation approaches.
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Affiliation(s)
- Sylvia J Gasparini
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307, Dresden, Germany
| | - Sílvia Llonch
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307, Dresden, Germany
| | - Oliver Borsch
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307, Dresden, Germany
| | - Marius Ader
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307, Dresden, Germany.
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Abstract
Human-induced pluripotent stem cells (hiPSCs) provide a personalized approach to study conditions and diseases including those of the eye that lack appropriate animal models to facilitate the development of novel therapeutics. Corneal disease is one of the most common causes of blindness. Hence, significant efforts are made to develop novel therapeutic approaches including stem cell-derived strategies to replace the diseased or damaged corneal tissues, thus restoring the vision. The use of adult limbal stem cells in the management of corneal conditions has been clinically successful. However, its limited availability and phenotypic plasticity necessitate the need for alternative stem cell sources to manage corneal conditions. Mesenchymal and embryonic stem cell-based approaches are being explored; nevertheless, their limited differentiation potential and ethical concerns have posed a significant hurdle in its clinical use. hiPSCs have emerged to fill these technical and ethical gaps to render clinical utility. In this review, we discuss and summarize protocols that have been devised so far to direct differentiation of human pluripotent stem cells (hPSCs) to different corneal cell phenotypes. With the summarization, our review intends to facilitate an understanding which would allow developing efficient and robust protocols to obtain specific corneal cell phenotype from hPSCs for corneal disease modeling and for the clinics to treat corneal diseases and injury.
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Affiliation(s)
| | - Rohit Shetty
- Cornea and Refractive Surgery, Narayana Nethralaya, Bengaluru, India
| | - Arkasubhra Ghosh
- GROW Research Laboratory, Narayana Nethralaya Foundation, Bengaluru, India
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42
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Generation and Applications of Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells. Stem Cells Int 2018; 2018:9601623. [PMID: 30154868 PMCID: PMC6091255 DOI: 10.1155/2018/9601623] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 06/12/2018] [Accepted: 06/20/2018] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are adult stem cells with fibroblast-like morphology and isolated from the bone marrow via plastic adhesion. Their multipotency and immunoregulatory properties make MSCs possible therapeutic agents, and an increasing number of publications and clinical trials have highlighted their potential in regenerative medicine. However, the finite proliferative capacity of MSCs limits their scalability and global dissemination as a standardized therapeutic product. Furthermore, adult tissue provenance could constrain accessibility, impinge on cellular potency, and incur greater exposure to disease-causing pathogens based on the donor. These issues could be circumvented by the derivation of MSCs from pluripotent stem cells. In this paper, we review methods that induce and characterize MSCs derived from induced pluripotent stem cells (iPSCs) and introduce MSC applications to disease modeling, pathogenic mechanisms, and drug discovery. We also discuss the potential applications of MSCs in regenerative medicine including cell-based therapies and issues that should be overcome before iPSC-derived MSC therapy will be applied in the clinic.
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43
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Eto S, Goto M, Soga M, Kaneko Y, Uehara Y, Mizuta H, Era T. Mesenchymal stem cells derived from human iPS cells via mesoderm and neuroepithelium have different features and therapeutic potentials. PLoS One 2018; 13:e0200790. [PMID: 30044827 PMCID: PMC6059447 DOI: 10.1371/journal.pone.0200790] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 07/03/2018] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) isolated from adult human tissues are capable of proliferating in vitro and maintaining their multipotency, making them attractive cell sources for regenerative medicine. However, the availability and capability of self-renewal under current preparation regimes are limited. Induced pluripotent stem cells (iPSCs) now offer an alternative, similar cell source to MSCs. Herein, we established new methods for differentiating hiPSCs into MSCs via mesoderm-like and neuroepithelium-like cells. Both derived MSC populations exhibited self-renewal and multipotency, as well as therapeutic potential in mouse models of skin wounds, pressure ulcers, and osteoarthritis. Interestingly, the therapeutic effects differ between the two types of MSCs in the disease models, suggesting that the therapeutic effect depends on the cell origin. Our results provide valuable basic insights for the clinical application of such cells.
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Affiliation(s)
- Shinya Eto
- Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Mizuki Goto
- Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
- Department of Dermatology, Faculty of Medicine, Oita University, Yufu, Japan
- * E-mail: (TE); (MG)
| | - Minami Soga
- Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Yumi Kaneko
- Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Yusuke Uehara
- Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hiroshi Mizuta
- Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Takumi Era
- Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
- * E-mail: (TE); (MG)
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44
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Stern JH, Tian Y, Funderburgh J, Pellegrini G, Zhang K, Goldberg JL, Ali RR, Young M, Xie Y, Temple S. Regenerating Eye Tissues to Preserve and Restore Vision. Cell Stem Cell 2018; 22:834-849. [PMID: 29859174 PMCID: PMC6492284 DOI: 10.1016/j.stem.2018.05.013] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ocular regenerative therapies are on track to revolutionize treatment of numerous blinding disorders, including corneal disease, cataract, glaucoma, retinitis pigmentosa, and age-related macular degeneration. A variety of transplantable products, delivered as cell suspensions or as preformed 3D structures combining cells and natural or artificial substrates, are in the pipeline. Here we review the status of clinical and preclinical studies for stem cell-based repair, covering key eye tissues from front to back, from cornea to retina, and including bioengineering approaches that advance cell product manufacturing. While recognizing the challenges, we look forward to a deep portfolio of sight-restoring, stem cell-based medicine. VIDEO ABSTRACT.
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Affiliation(s)
- Jeffrey H Stern
- Neural Stem Cell Institute, Rensselaer, NY 12144, USA; Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA
| | - Yangzi Tian
- Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road, Albany, NY 12203, USA
| | - James Funderburgh
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Graziella Pellegrini
- Centre for Regenerative Medicine, University of Modena and Reggio Emilia, via G.Gottardi 100, 41125 Modena, Italy
| | - Kang Zhang
- Shiley Eye Institute and Institute for Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University and Guangzhou Regenerative Medicine and Health Laboratory, Guangzhou 510060, China
| | - Jeffrey L Goldberg
- Byers Eye Institute at Stanford University, 2452 Watson Court, Palo Alto, CA 94303, USA
| | - Robin R Ali
- Department of Genetics, University College London Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK; NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, City Road, London EC1V 2PD, UK; Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA
| | - Michael Young
- The Schepens Eye Research Institute, Massachusetts Eye and Ear, an affiliate of Harvard Medical School, Boston, MA 02114, USA
| | - Yubing Xie
- Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road, Albany, NY 12203, USA
| | - Sally Temple
- Neural Stem Cell Institute, Rensselaer, NY 12144, USA; Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA.
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45
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Verbakel SK, van Huet RAC, Boon CJF, den Hollander AI, Collin RWJ, Klaver CCW, Hoyng CB, Roepman R, Klevering BJ. Non-syndromic retinitis pigmentosa. Prog Retin Eye Res 2018; 66:157-186. [PMID: 29597005 DOI: 10.1016/j.preteyeres.2018.03.005] [Citation(s) in RCA: 604] [Impact Index Per Article: 86.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 03/20/2018] [Accepted: 03/22/2018] [Indexed: 12/23/2022]
Abstract
Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. RP is a leading cause of visual disability, with a worldwide prevalence of 1:4000. Although the majority of RP cases are non-syndromic, 20-30% of patients with RP also have an associated non-ocular condition. RP typically manifests with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors; central vision loss occurs later in life due to cone dysfunction. Photoreceptor function measured with an electroretinogram is markedly reduced or even absent. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging show a progressive loss of outer retinal layers and altered lipofuscin distribution in a characteristic pattern. Over the past three decades, a vast number of disease-causing variants in more than 80 genes have been associated with non-syndromic RP. The wide heterogeneity of RP makes it challenging to describe the clinical findings and pathogenesis. In this review, we provide a comprehensive overview of the clinical characteristics of RP specific to genetically defined patient subsets. We supply a unique atlas with color fundus photographs of most RP subtypes, and we discuss the relevant considerations with respect to differential diagnoses. In addition, we discuss the genes involved in the pathogenesis of RP, as well as the retinal processes that are affected by pathogenic mutations in these genes. Finally, we review management strategies for patients with RP, including counseling, visual rehabilitation, and current and emerging therapeutic options.
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Affiliation(s)
- Sanne K Verbakel
- Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ramon A C van Huet
- Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Camiel J F Boon
- Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands; Department of Ophthalmology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Anneke I den Hollander
- Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Rob W J Collin
- Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Caroline C W Klaver
- Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Carel B Hoyng
- Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ronald Roepman
- Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - B Jeroen Klevering
- Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
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Morishima Y, Azuma F, Kashiwase K, Matsumoto K, Orihara T, Yabe H, Kato S, Kato K, Kai S, Mori T, Nakajima K, Morishima S, Satake M, Takanashi M, Yabe T. Risk of HLA Homozygous Cord Blood Transplantation: Implications for Induced Pluripotent Stem Cell Banking and Transplantation. Stem Cells Transl Med 2017; 7:173-179. [PMID: 29274116 PMCID: PMC5788882 DOI: 10.1002/sctm.17-0169] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 11/13/2017] [Indexed: 01/22/2023] Open
Abstract
Clinical application of induced pluripotent stem cells (iPS) in autologous settings has just begun. To overcome the high time and cost barriers in the individual production of autologous iPS, the use of allogeneic iPS with a homozygous human leukocyte antigen (HLA) haplotype (HLA‐homo HP) has been proposed. Cord blood transplantation (CBT) is a suitable model for evaluating the allogeneic immunogenicity of iPS transplantation from HLA‐homo donors. We analyzed 1,374 Japanese single cord blood transplant pairs who were retrospectively typed as HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQB1, and ‐DPB1. Among these, six pairs with donor HLA homo—patient‐HLA hetero (homo‐hetero) were found, all of which showed favorable neutrophil engraftment. Multivariate analysis revealed a significantly elevated engraftment risk (HR = 1.59) compared with hetero‐hetero pairs with HLA 1‐2 locus mismatch (789 pts) and comparative risk (HR = 1.23) compared with hetero‐hetero pairs with 0 mismatch (104 pts). These results for CBT with HLA‐homo HP cord blood carry an important implication, namely the possibility that HLA‐homo iPS transplantation results in favorable engraftment. Furthermore, we obtained detailed information on HLA alleles and haplotypes of HLA‐homo. All donor HLA‐homo HPs had a common specific ethnicity and high conservation of the HLA region, and one of two patient heterogeneous HPs invariably shared the same HP as donor HLA‐homo HP, and another non‐shared patient HP was mismatched with 1 to 4 HLA alleles of HLA‐A, ‐B, ‐C, and ‐DRB1 loci in the GVH direction. These findings indicate that patients possessing a single common HLA haplotype have a higher chance of yielding HLA‐homo iPS. Stem Cells Translational Medicine2018;7:173–179
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Affiliation(s)
- Yasuo Morishima
- Central Japan Cord Blood Bank, Seto, Japan.,Aichi Cancer Center Research Institute, Nagoya, Japan.,Aichi Medical University School of Medicine, Nagakute, Japan
| | - Fumihiro Azuma
- Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan
| | - Koichi Kashiwase
- Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan
| | | | | | | | | | - Koji Kato
- Central Japan Cord Blood Bank, Seto, Japan
| | - Shunro Kai
- Hyogo Cord Blood Bank, Nishinomiya, Japan
| | - Tetsuo Mori
- Japanese Red Cross Kyushu Cord Blood Bank, Chikushino, Japan
| | - Kazunori Nakajima
- Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan
| | - Satoko Morishima
- Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology. Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
| | | | | | - Toshio Yabe
- Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan
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47
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Yoshihara M, Hayashizaki Y, Murakawa Y. Genomic Instability of iPSCs: Challenges Towards Their Clinical Applications. Stem Cell Rev Rep 2017; 13:7-16. [PMID: 27592701 PMCID: PMC5346115 DOI: 10.1007/s12015-016-9680-6] [Citation(s) in RCA: 194] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Induced pluripotent stem cells (iPSCs) are a type of pluripotent stem cells generated directly from mature cells through the introduction of key transcription factors. iPSCs can be propagated and differentiated into many cell types in the human body, holding enormous potential in the field of regenerative medicine. However, genomic instability of iPSCs has been reported with the advent of high-throughput technologies such as next-generation sequencing. The presence of genetic variations in iPSCs has raised serious safety concerns, hampering the advancement of iPSC-based novel therapies. Here we summarize our current knowledge on genomic instability of iPSCs, with a particular focus on types of genetic variations and their origins. Importantly, it remains elusive whether genetic variations in iPSCs can be an actual risk factor for adverse effects including malignant outgrowth. Furthermore, we discuss novel approaches to generate iPSCs with fewer genetic variations. Lastly, we outline the safety issues and monitoring strategies of iPSCs in clinical settings.
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Affiliation(s)
- Masahito Yoshihara
- Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa, Japan.,Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | | | - Yasuhiro Murakawa
- Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa, Japan. .,RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama, Japan.
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48
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Low immunogenicity of mouse induced pluripotent stem cell-derived neural stem/progenitor cells. Sci Rep 2017; 7:12996. [PMID: 29021610 PMCID: PMC5636829 DOI: 10.1038/s41598-017-13522-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 09/25/2017] [Indexed: 12/11/2022] Open
Abstract
Resolving the immunogenicity of cells derived from induced pluripotent stem cells (iPSCs) remains an important challenge for cell transplant strategies that use banked allogeneic cells. Thus, we evaluated the immunogenicity of mouse fetal neural stem/progenitor cells (fetus-NSPCs) and iPSC-derived neural stem/progenitor cells (iPSC-NSPCs) both in vitro and in vivo. Flow cytometry revealed the low expression of immunological surface antigens, and these cells survived in all mice when transplanted syngeneically into subcutaneous tissue and the spinal cord. In contrast, an allogeneic transplantation into subcutaneous tissue was rejected in all mice, and allogeneic cells transplanted into intact and injured spinal cords survived for 3 months in approximately 20% of mice. In addition, cell survival was increased after co-treatment with an immunosuppressive agent. Thus, the immunogenicity and post-transplantation immunological dynamics of iPSC-NSPCs resemble those of fetus-NSPCs.
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49
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Zhang J, Chu LF, Hou Z, Schwartz MP, Hacker T, Vickerman V, Swanson S, Leng N, Nguyen BK, Elwell A, Bolin J, Brown ME, Stewart R, Burlingham WJ, Murphy WL, Thomson JA. Functional characterization of human pluripotent stem cell-derived arterial endothelial cells. Proc Natl Acad Sci U S A 2017; 114:E6072-E6078. [PMID: 28696312 PMCID: PMC5544294 DOI: 10.1073/pnas.1702295114] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Here, we report the derivation of arterial endothelial cells from human pluripotent stem cells that exhibit arterial-specific functions in vitro and in vivo. We combine single-cell RNA sequencing of embryonic mouse endothelial cells with an EFNB2-tdTomato/EPHB4-EGFP dual reporter human embryonic stem cell line to identify factors that regulate arterial endothelial cell specification. The resulting xeno-free protocol produces cells with gene expression profiles, oxygen consumption rates, nitric oxide production levels, shear stress responses, and TNFα-induced leukocyte adhesion rates characteristic of arterial endothelial cells. Arterial endothelial cells were robustly generated from multiple human embryonic and induced pluripotent stem cell lines and have potential applications for both disease modeling and regenerative medicine.
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Affiliation(s)
- Jue Zhang
- Regenerative Biology, Morgridge Institute for Research, Madison, WI 53715
| | - Li-Fang Chu
- Regenerative Biology, Morgridge Institute for Research, Madison, WI 53715
| | - Zhonggang Hou
- Regenerative Biology, Morgridge Institute for Research, Madison, WI 53715
- Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Michael P Schwartz
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706
| | - Timothy Hacker
- Cardiovascular Physiology Core Facility, University of Wisconsin-Madison, Madison, WI 53705
| | - Vernella Vickerman
- Regenerative Biology, Morgridge Institute for Research, Madison, WI 53715
| | - Scott Swanson
- Regenerative Biology, Morgridge Institute for Research, Madison, WI 53715
| | - Ning Leng
- Regenerative Biology, Morgridge Institute for Research, Madison, WI 53715
- Biostatistics, Genentech, San Francisco, CA 94080
| | - Bao Kim Nguyen
- Regenerative Biology, Morgridge Institute for Research, Madison, WI 53715
| | - Angela Elwell
- Regenerative Biology, Morgridge Institute for Research, Madison, WI 53715
| | - Jennifer Bolin
- Regenerative Biology, Morgridge Institute for Research, Madison, WI 53715
| | - Matthew E Brown
- Regenerative Biology, Morgridge Institute for Research, Madison, WI 53715
- Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705
| | - Ron Stewart
- Regenerative Biology, Morgridge Institute for Research, Madison, WI 53715
| | - William J Burlingham
- Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705
| | - William L Murphy
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706
- Department of Orthopedics and Rehabilitation, University of Wisconsin-Madison, Madison, 53705
| | - James A Thomson
- Regenerative Biology, Morgridge Institute for Research, Madison, WI 53715;
- Department of Cell & Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53706
- Department of Molecular, Cellular, & Developmental Biology, University of California, Santa Barbara, CA 93117
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50
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Characterization of Mesenchymal Stem Cell-Like Cells Derived From Human iPSCs via Neural Crest Development and Their Application for Osteochondral Repair. Stem Cells Int 2017; 2017:1960965. [PMID: 28607560 PMCID: PMC5451770 DOI: 10.1155/2017/1960965] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 04/03/2017] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cells (MSCs) derived from induced pluripotent stem cells (iPSCs) are a promising cell source for the repair of skeletal disorders. Recently, neural crest cells (NCCs) were reported to be effective for inducing mesenchymal progenitors, which have potential to differentiate into osteochondral lineages. Our aim was to investigate the feasibility of MSC-like cells originated from iPSCs via NCCs for osteochondral repair. Initially, MSC-like cells derived from iPSC-NCCs (iNCCs) were generated and characterized in vitro. These iNCC-derived MSC-like cells (iNCMSCs) exhibited a homogenous population and potential for osteochondral differentiation. No upregulation of pluripotent markers was detected during culture. Second, we implanted iNCMSC-derived tissue-engineered constructs into rat osteochondral defects without any preinduction for specific differentiation lineages. The implanted cells remained alive at the implanted site, whereas they failed to repair the defects, with only scarce development of osteochondral tissue in vivo. With regard to tumorigenesis, the implanted cells gradually disappeared and no malignant cells were detected throughout the 2-month follow-up. While this study did not show that iNCMSCs have efficacy for repair of osteochondral defects when implanted under undifferentiated conditions, iNCMSCs exhibited good chondrogenic potential in vitro under appropriate conditions. With further optimization, iNCMSCs may be a new source for tissue engineering of cartilage.
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