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Cell therapy products (CTP) derived from pluripotent stem cells (iPSCs) may constitute a renewable, specifically differentiated source of cells to potentially cure patients with neurodegenerative disorders. However, the immunogenicity of CTP remains a major issue for therapeutic approaches based on transplantation of non-autologous stem cell-derived neural grafts. Despite its considerable side-effects, long-term immunosuppression, appears indispensable to mitigate neuro-inflammation and prevent rejection of allogeneic CTP. Matching iPSC donors’ and patients’ HLA haplotypes has been proposed as a way to access CTP with enhanced immunological compatibility, ultimately reducing the need for immunosuppression. In the present work, we challenge this paradigm by grafting autologous, MHC-matched and mis-matched neuronal grafts in a primate model of Huntington’s disease. Unlike previous reports in unlesioned hosts, we show that in the absence of immunosuppression MHC matching alone is insufficient to grant long-term survival of neuronal grafts in the lesioned brain. Matching iPSC donors’ and patients’ HLA haplotypes has been proposed as a way to generate cell therapy products with enhanced immunological compatibility. Here the authors show that MHC matching alone is insufficient to grant long-term survival of neuronal grafts in the lesioned brain of non-human primates.

IntroductionGStemHep cells are human cryopreserved hepatic progenitors derived from pluripotent of stem cells (GStem cells) using a cGMP-compliant protocol. They were highly effective in rescuing mice from acute liver failure.MethodsThe objective of this study was to analyze the immunogenicity and immunoregulatory properties of GStemHep cells.ResultsAs compared to GStem cells, GStemHep cells showed complete loss of HLA-I (ABC) and they lacked of expression of HLA-II, HLA-G, HLA-E and PD-L1. GStemHep cells also showed increased expression of CD47, maintained high expression of indoleamine 2,3-dioxygenase (IDO) and heme oxygenase-1 (HO-1) and reduced expression of CD200. In comparison with GStem cells, GStemHep cultured in inflammatory conditions increased the expression of PD-L1, CD200, HO-1, HLA-E, CD47 and HLA-I (ABC) as well as maintained expression of IDO and were negative for HLA-II and HLA-G. GStemHep culture in basal or inflammatory conditions has a low or absent immunogenic activity on T cells, associated to a suppressive effect on proliferation partially mediated by IDO. We observed phagocytosis of GStemHep by macrophages that was partially inhibited by CD47 expression. NK cells were activated by resting GStemHep cells. Upon culture in inflammatory conditions that induced expression of HLA-I molecules in GStemHep cells NK cell activation was reduced. Thus, GStemHep cells are partially hypoimmune cells due to the expression of several immune checkpoint inhibitors and the absence of HLA-I molecules. In inflammatory conditions, the expression of several of these molecules was increased but also of HLA-I that could be immunogenic for T cells but it was inhibitory for NK cells.DiscussionGStemHep cells show a favorable immunological profile for their use as allogeneic off-the shelf treatment of liver diseases with loss of hepatocyte function.

Recent outstanding clinical results produced by engineered T cells, including chimeric antigen receptors, have already facilitated further research that broadens their applicability. One such direction is to explore new T cell sources for allogeneic “off‐the‐shelf” adoptive immunotherapy. Human pluripotent stem cells could serve as an alternative cell source for this purpose due to their unique features of infinite propagation ability and pluripotency. Here, we describe the current state of engineered T cell transfer with the focus on cell manufacturing processes and the potentials and challenges of induced pluripotent stem cell‐derived T cells as a starting material to construct off‐the‐shelf T‐cell banks. Key steps for differentiation of T cells from hematopoietic pluripotent stem cells. The steps can be divided into three stages: (i) hematopoietic induction; (ii) T cell differentiation; and (iii) T cell maturation. Each stage can be subdivided into several steps.

The derivation of induced pluripotent stem cells (iPSCs) over a decade ago sparked widespread enthusiasm for the development of new models of human disease, enhanced platforms for drug discovery and more widespread use of autologous cell-based therapy. Early studies using directed differentiation of iPSCs frequently uncovered cell-level phenotypes in monogenic diseases, but translation to tissue-level and organ-level diseases has required development of more complex, 3D, multicellular systems. Organoids and human–rodent chimaeras more accurately mirror the diverse cellular ecosystems of complex tissues and are being applied to iPSC disease models to recapitulate the pathobiology of a broad spectrum of human maladies, including infectious diseases, genetic disorders and cancer.Enthusiasm for patient-specific therapies based on induced pluripotent stem cells (iPSCs) has risen in parallel with rapid advances in genome editing. This Review summarizes the progress in iPSC-based disease modelling over the past decade, with a focus on 3D organoid systems and chimeric models being exploited for new therapeutic approaches.

Rejection of iPS cells Induced pluripotent stem (iPS) cells, which are produced by reprogramming fully differentiated adult cells back to an embryonic-like state by expression of specific genes, have important therapeutic potential. As iPS cells are derived entirely from the patient, one hoped-for advantage of using them in therapy is that there should be no immune rejection. Now it seems this might not be the case. In experiments in which iPS cells were reprogrammed using a retroviral or non-integrative episomal approach and then transplanted into mice, teratoma cells derived from the iPS cells were rejected by the immune system, even in syngeneic recipients. This finding suggests that altered gene expression in some cells differentiated from iPS cells can induce T-cell-dependent immune responses. The authors suggest that the immunogenicity of therapeutically valuable cells derived from patient-specific iPS cells should be evaluated before they are used in any clinical applications. Induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells with defined factors, hold great promise for regenerative medicine as the renewable source of autologous cells 1 , 2 , 3 , 4 , 5 . Whereas it has been generally assumed that these autologous cells should be immune-tolerated by the recipient from whom the iPSCs are derived, their immunogenicity has not been vigorously examined. We show here that, whereas embryonic stem cells (ESCs) derived from inbred C57BL/6 (B6) mice can efficiently form teratomas in B6 mice without any evident immune rejection, the allogeneic ESCs from 129/SvJ mice fail to form teratomas in B6 mice due to rapid rejection by recipients. B6 mouse embryonic fibroblasts (MEFs) were reprogrammed into iPSCs by either retroviral approach (ViPSCs) or a novel episomal approach (EiPSCs) that causes no genomic integration. In contrast to B6 ESCs, teratomas formed by B6 ViPSCs were mostly immune-rejected by B6 recipients. In addition, the majority of teratomas formed by B6 EiPSCs were immunogenic in B6 mice with T cell infiltration, and apparent tissue damage and regression were observed in a small fraction of teratomas. Global gene expression analysis of teratomas formed by B6 ESCs and EiPSCs revealed a number of genes frequently overexpressed in teratomas derived from EiPSCs, and several such gene products were shown to contribute directly to the immunogenicity of the B6 EiPSC-derived cells in B6 mice. These findings indicate that, in contrast to derivatives of ESCs, abnormal gene expression in some cells differentiated from iPSCs can induce T-cell-dependent immune response in syngeneic recipients. Therefore, the immunogenicity of therapeutically valuable cells derived from patient-specific iPSCs should be evaluated before any clinic application of these autologous cells into the patients.

Expression of the minimally polymorphic HLA-E molecule prevents NK-cell-mediated rejection of cells lacking expression of HLA-A, B and C. Polymorphisms in the human leukocyte antigen (HLA) class I genes can cause the rejection of pluripotent stem cell (PSC)-derived products in allogeneic recipients. Disruption of the Beta-2 Microglobulin ( B2M ) gene eliminates surface expression of all class I molecules, but leaves the cells vulnerable to lysis by natural killer (NK) cells. Here we show that this 'missing-self' response can be prevented by forced expression of minimally polymorphic HLA-E molecules. We use adeno-associated virus (AAV)-mediated gene editing to knock in HLA-E genes at the B2M locus in human PSCs in a manner that confers inducible, regulated, surface expression of HLA-E single-chain dimers (fused to B2M) or trimers (fused to B2M and a peptide antigen), without surface expression of HLA-A, B or C. These HLA-engineered PSCs and their differentiated derivatives are not recognized as allogeneic by CD8 + T cells, do not bind anti-HLA antibodies and are resistant to NK-mediated lysis. Our approach provides a potential source of universal donor cells for applications where the differentiated derivatives lack HLA class II expression.

Immune rejection may limit the therapeutic use of induced pluripotent stem cells (iPSCs); here, terminally differentiated mouse iPSCs are shown to generate negligible immune rejection in their host. No immune reaction to iPSCs Induced pluripotent stem cells (iPSCs) derived from a patient's own somatic cells could have great therapeutic potential. The hope is that iPSC-derived differentiated cells would avoid any immunogenic responses. In this study, Masumi Abe and colleagues assess the immunogenicity of skin and bone marrow tissues derived from a large set of isogenic mouse embryonic stem cell and iPSC lines. Their results are consistent with negligible immune rejection by the host. The advantages of using induced pluripotent stem cells (iPSCs) instead of embryonic stem (ES) cells in regenerative medicine centre around circumventing concerns about the ethics of using ES cells and the likelihood of immune rejection of ES-cell-derived tissues 1 , 2 . However, partial reprogramming and genetic instabilities in iPSCs 3 , 4 , 5 , 6 could elicit immune responses in transplant recipients even when iPSC-derived differentiated cells are transplanted. iPSCs are first differentiated into specific types of cells in vitro for subsequent transplantation. Although model transplantation experiments have been conducted using various iPSC-derived differentiated tissues 7 , 8 , 9 , 10 and immune rejections have not been observed, careful investigation of the immunogenicity of iPSC-derived tissue is becoming increasingly critical, especially as this has not been the focus of most studies done so far. A recent study reported immunogenicity of iPSC- but not ES-cell-derived teratomas 11 and implicated several causative genes. Nevertheless, some controversy has arisen regarding these findings 12 . Here we examine the immunogenicity of differentiated skin and bone marrow tissues derived from mouse iPSCs. To ensure optimal comparison of iPSCs and ES cells, we established ten integration-free iPSC and seven ES-cell lines using an inbred mouse strain, C57BL/6. We observed no differences in the rate of success of transplantation when skin and bone marrow cells derived from iPSCs were compared with ES-cell-derived tissues. Moreover, we observed limited or no immune responses, including T-cell infiltration, for tissues derived from either iPSCs or ES cells, and no increase in the expression of the immunogenicity-causing Zg16 and Hormad1 genes in regressing skin and teratoma tissues. Our findings suggest limited immunogenicity of transplanted cells differentiated from iPSCs and ES cells.

Ectopic expression of transcription factors can reprogram somatic cells to a pluripotent state. However, most of the studies used skin fibroblasts as the starting population for reprogramming, which usually take weeks for expansion from a single biopsy. We show here that induced pluripotent stem (iPS) cells can be generated from adult human adipose stem cells (hASCs) freshly isolated from patients. Furthermore, iPS cells can be readily derived from adult hASCs in a feeder-free condition, thereby eliminating potential variability caused by using feeder cells. hASCs can be safely and readily isolated from adult humans in large quantities without extended time for expansion, are easy to maintain in culture, and therefore represent an ideal autologous source of cells for generating individual-specific iPS cells.

Use of clinical-grade human induced pluripotent stem cell (iPSC) lines as a starting material for the generation of cellular therapeutics requires demonstration of comparability of lines derived from different individuals and in different facilities. This requires agreement on the critical quality attributes of such lines and the assays that should be used. Working from established recommendations and guidance from the International Stem Cell Banking Initiative for human embryonic stem cell banking, and concentrating on those issues more relevant to iPSCs, a series of consensus workshops has made initial recommendations on the minimum dataset required to consider an iPSC line of clinical grade, which are outlined in this report. Continued evolution of this field will likely lead to revision of these guidelines on a regular basis.

Dopaminergic progenitor cells that were derived from a patient’s induced pluripotent stem cells were implanted bilaterally in the putamen. Clinical and PET studies suggested survival of the cells and clinical stability over a period of 24 months, without dyskinesias.