Engineering the next generation of cell-based therapeutics

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(9), P. 655 - 675

Published: May 30, 2022

Language: Английский

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Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes

Cell stem cell, Journal Year: 2023, Volume and Issue: 30(5), P. 530 - 548

Published: May 1, 2023

The generation of islet-like endocrine clusters from human pluripotent stem cells (hPSCs) has the potential to provide an unlimited source insulin-producing β for treatment diabetes. In order this cell therapy become widely adopted, highly functional and well-characterized cell-derived islets (SC-islets) need be manufactured at scale. Furthermore, successful SC-islet replacement strategies should prevent significant loss immediately following transplantation avoid long-term immune rejection. This review highlights most recent advances in characterization SC-islets as well ensure graft viability safety after transplantation.

Language: Английский

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Hypoimmune induced pluripotent stem cells survive long term in fully immunocompetent, allogeneic rhesus macaques

Nature Biotechnology, Journal Year: 2023, Volume and Issue: 42(3), P. 413 - 423

Published: May 8, 2023

Abstract Genetic engineering of allogeneic cell therapeutics that fully prevents rejection by a recipient’s immune system would abolish the requirement for immunosuppressive drugs or encapsulation and support large-scale manufacturing off-the-shelf products. Previously, we generated mouse human hypoimmune pluripotent (HIP) stem cells depleting HLA class I II molecules overexpressing CD47 ( B2M −/− CIITA + ). To determine whether this strategy is successful in non-human primates, engineered rhesus macaque HIP transplanted them intramuscularly into four macaques. The survived unrestricted 16 weeks immunocompetent recipients differentiated several lineages, whereas wild-type were vigorously rejected. We also endocrinologically active pancreatic islet showed they immunocompetent, diabetic humanized mice 4 ameliorated diabetes. HIP-edited primary islets 40 an recipient without immunosuppression, unedited quickly

Language: Английский

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Human hypoimmune primary pancreatic islets avoid rejection and autoimmunity and alleviate diabetes in allogeneic humanized mice

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(691)

Published: April 12, 2023

Transplantation of allogeneic pancreatic donor islets has successfully been performed in selected patients with difficult-to-control insulin-dependent diabetes and impaired awareness hypoglycemia (IAH). However, the required systemic immunosuppression associated this procedure prevents cell replacement therapy from more widespread adoption larger patient populations. We report editing primary human islet cells to hypoimmune HLA class I- II-negative CD47-overexpressing phenotype their reaggregation into HIP pseudoislets (p-islets). Human p-islets were shown survive, engraft, ameliorate immunocompetent, allogeneic, diabetic humanized mice. p-islet further avoid autoimmune killing autologous, The survival endocrine function not by contamination unedited or partially edited within p-islets. eliminated quickly reliably model using a CD47-targeting antibody, thus providing safety strategy case exert toxicity future clinical setting. for which no is potential lead wider help IAH history severe hypoglycemic events achieve insulin independence.

Language: Английский

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MorPhiC Consortium: towards functional characterization of all human genes

Nature, Journal Year: 2025, Volume and Issue: 638(8050), P. 351 - 359

Published: Feb. 12, 2025

Language: Английский

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Bioprinting of bespoke islet-specific niches to promote maturation of stem cell-derived islets

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 7, 2025

Pancreatic islets are densely packed cellular aggregates containing various hormonal cell types essential for blood glucose regulation. Interactions among these cells markedly affect the glucoregulatory functions of along with surrounding niche and pancreatic tissue-specific geometrical organization. However, stem (SC)-derived generated in vitro often lack three-dimensional extracellular microenvironment peri-vasculature, which leads to immaturity SC-derived islets, reducing their ability detect fluctuations insulin release. Here, we bioengineer vivo-like niches by optimizing combination matrix basement membrane proteins utilizing bioprinting-based guidance recreate spatial pattern islet peripheries. The bioprinted islet-specific promotes coordinated interactions between vasculature, supporting structural functional features resembling native islets. Our strategy not only improves functionality but also offers significant potential advancing research on development, maturation, diabetic disease modeling, future implications translational applications.

Language: Английский

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Stem cells differentiation into insulin-producing cells (IPCs): recent advances and current challenges

Stem Cell Research & Therapy, Journal Year: 2022, Volume and Issue: 13(1)

Published: July 15, 2022

Abstract Type 1 diabetes mellitus (T1D) is a chronic disease characterized by an autoimmune destruction of insulin-producing β -pancreatic cells. Although many advances have been achieved in T1D treatment, current therapy strategies are often unable to maintain perfect control glycemic levels. Several studies searching for new and improved methodologies expansion -cell cultures vitro increase the supply these cells pancreatic islets replacement therapy. A promising approach consists differentiation stem into (IPCs) sufficient number functional status be transplanted. Differentiation protocols designed using consecutive cytokines or signaling modulator treatments, at specific dosages, activate inhibit main pathways that induced pluripotent (iPSCs) -cells. Here, we provide overview approaches achievements obtaining cell-derived -cells numerous challenges, which still need overcome achieve this goal. Clinical translation cells-derived efficient maintenance long-term euglycemia remains major issue. Therefore, research efforts directed final steps differentiation, aiming production mature integration interdisciplinary fields generate cell capable reversing clinical outcome T1D.

Language: Английский

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Single-nucleus multi-omics of human stem cell-derived islets identifies deficiencies in lineage specification

Nature Cell Biology, Journal Year: 2023, Volume and Issue: 25(6), P. 904 - 916

Published: May 15, 2023

Abstract Insulin-producing β cells created from human pluripotent stem have potential as a therapy for insulin-dependent diabetes, but cell-derived islets (SC-islets) still differ their in vivo counterparts. To better understand the state of cell types within SC-islets and identify lineage specification deficiencies, we used single-nucleus multi-omic sequencing to analyse chromatin accessibility transcriptional profiles primary islets. Here provide an analysis that enabled derivation gene lists activity identifying each SC-islet type compared with Within SC-islets, found difference between awry enterochromaffin-like is gradient states rather than stark identity. Furthermore, transplantation improved cellular identities overtime, while long-term vitro culture did not. Collectively, our results highlight importance landscapes during islet maturation.

Language: Английский

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Deciphering early human pancreas development at the single-cell level

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Sept. 2, 2023

Understanding pancreas development can provide clues for better treatments of pancreatic diseases. However, the molecular heterogeneity and developmental trajectory early human are poorly explored. Here, we performed large-scale single-cell RNA sequencing assay transposase accessible chromatin embryonic tissue obtained from first-trimester embryos. We unraveled heterogeneity, trajectories regulatory networks major cell types. The results reveal that dorsal multipotent cells in humans exhibit different gene expression patterns than ventral cells. Pancreato-biliary progenitors generate were identified. Notch MAPK signals mesenchymal regulate differentiation into trunk duct Notably, identified endocrine progenitor subclusters with potentials. Although largely conserved between mice, some distinct have also been Overall, a comprehensive landscape to understand its lineage transitions complexity.

Language: Английский

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Standardized production of hPSC-derived cardiomyocyte aggregates in stirred spinner flasks

Nature Protocols, Journal Year: 2024, Volume and Issue: 19(7), P. 1911 - 1939

Published: March 28, 2024

Language: Английский

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