Transplantation-induced reprogramming determines successful hepatocyte engraftment
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PROVIDER: PRJNA1150161 | ENA |
REPOSITORIES: ENA
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Project description:While demonstrated safety and efficacy in treating liver diseases, hepatocyte-based therapy faces the challenge of limited engraftment of transplanted hepatocytes (Tx-Heps) in clinical settings, akin to issues encountered in cell therapy for other solid organs. Here, we identified a conserved reprogramming state of Tx-Heps during engraftment, marked by the activation of liver progenitor genes and bipotential differentiation capacity. Transplantation reprogramming of Tx-Heps is crucial for successful engraftment, as proven by transplantation failure upon hepatocyte-specific ablation of Arid1a, which is required for Tx-Hep reprogramming. To validate translational potential, we artificially induced Tx-Hep reprogramming by in vivo treatment of either IL6 or IC7, a chimeric IL6 family protein, both of which significantly enhance hepatocyte engraftment. Our findings unveil early-stage cell fate reprogramming during transplantation and also propose a promising strategy to augment hepatocyte engraftment, which is an interesting framework to be studied in cell transplantation for other solid organs.
2025-08-18 | GSE275278 | GEO
Project description:Hepatocyte transplantation has shown promise for genetic diseases but has mixed efficacy for acute and severe liver injury. Limited cell engraftment and poor function of donor hepatocytes in recipient liver are significant hurdles for clinical efficacy. Hepatocyte senescence is a key feature of many liver diseases. Senescence-driven liver injury could be induced in Ahcre+Mdm2fl/fl mice in controlled and predictable levels through excision of hepatocyte Mdm2. Host senescence and injury was a requirement for initial donor hepatocyte engraftment and repopulation, but too much was inhibitory to this. Long-term expansion of transplanted hepatocytes improved histological features of injury and liver function. However graft function could spontaneously decline due to transmission of senescence from host to donor cells. Modification of the host niche prior to transplantation with senotherapeutic drug ABT737 improved donor cell proliferative capacity. Targeting paracrine senescence may be a way to improve donor hepatocyte function, optimise therapy and guide translation into the clinics.
2025-01-31 | GSE240081 | GEO
Project description:Host senescence determines the success of hepatocyte transplantation in a mouse model of liver injury
| PRJNA1002262 | ENA
Project description:Restoration of hematopoiesis upon bone marrow (BM) transplantation relies on the engraftment, expansion and function of transplanted hematopoietic stem cells (HSC). However, the number of donorâderived HSC typically remain much below that present in normal individuals and this likely limits and delays hematopoietic recovery. HSC depend on supportive stromal niches, however, whether the preâconditioning required for BM transplantation damages this stromal niche has not been evaluated extensively. Using mouse models, we now find that that BM stroma cells (BMSC) are severely and permanently damaged by preâconditioning. Transplantation of primary but not cultured BMSC quantitatively reconstitutes stroma function in vivo, which is mediated by a multipotent CD73+ CD105â Sca1+ BMSC subpopulation. BMSC coâtransplantation significantly ameliorates clinical side effects of BM transplantation and doubles expansion of functional, donorâ derived HSC, demonstrating the potential of stroma transplantation to improve HSC transplantation. Purified CD45âTer119âCD73+ CD105â and CD45âTer119âCD73+ CD105+ cells were directly sorted on lysis buffer with FACS Aria 2 in triplicate.
2016-09-01 | E-GEOD-79091 | biostudies-arrayexpress
Project description:Stromal Repair via Long-term Engraftment of Primary Bone Marrow Stroma Improves Hematopoietic Stem Cell Transplantation
2017-07-02 | GSE79091 | GEO
Project description:Engraftment of donor cells is a prerequisite to successful allogeneic hematopoietic stem cell transplantation. However, it has been poorly characterized in detail both in experimental models and in human. Bone marrow examination by mass cytometry in 26 patients with myeloid malignancies and 20 healthy donors provides evidence that the proportions of myeloid and B-cell progenitors profoundly differed as compared to healthy controls with a shift toward terminal myeloid differentiation and sharp decrease of myeloid and B-cell progenitors. Principal component analysis clearly separated in 2 recipient groups (R1 and R2) driven by previous GVHD (in R2 patients). We then used single cell CITEseq to decipher donor cell engraftment in 10/26 patients (compared with 4 healthy donors). Forty-one clusters were resolved encompassing all bone marrow cellular components. Projection of patients and R1 and R2 showed drastic segregation of the 2 patient groups which were highly significant different repartition in a compositional analysis. In R2 patients sustained engraftment relied on only 10 clusters that included only committed myeloid progenitors, one stem-cell memory T-cell cluster and activated NK-cell clusters. Gene expression hallmarks disclosed repeatedly similar pathway in transplant recipients, namely, TNFα signaling via NFĸ, interferonƔ response, and allograft rejection. Thus, the cellular composition of the engrafted bone marrow in human is strongly influenced by T-cell mediated processes and inflammation leading to an emergency hematopoiesis.
2024-10-01 | GSE249722 | GEO
Project description:Because of the fragility of isolated hepatocytes, extremely poor engraftment of transplanted hepatocytes remains a severe issue in hepatocyte transplantation. Therefore, improving hepatocyte engraftment is necessary to establish hepatocyte transplantation as a standard therapy. Since the pancreatic islets are known to have favorable autocrine effects, we hypothesized that the transplanted islets might influence not only the islets but also the nearby hepatocytes, subsequently promoting engraftment. We evaluated the effects of islet co-transplantation using an analbuminemic rat model (in vivo model). Furthermore, we established a mimicking in vitro model to investigate the underlying mechanisms. In an in vivo model, the hepatocyte engraftment was significantly improved only when the islets were co-transplanted to the nearby hepatocytes (p < 0.001). Moreover, the transplanted hepatocytes appeared to penetrate the renal parenchyma together with the co-transplanted islets. In an in vitro model, the viability of cultured hepatocytes was also improved by coculture with pancreatic islets. Of particular interest, the coculture supernatant alone could also exert beneficial effects comparable to islet coculture. Although insulin, VEGF, and GLP-1 were selected as candidate crucial factors using the Bio-Plex system, beneficial effects were partially counteracted by anti-insulin receptor antibodies. In conclusion, this study demonstrated that islet co-transplantation improves hepatocyte engraftment, most likely due to continuously secreted crucial factors, such as insulin, in combination with providing favorable circumstances for hepatocyte engraftment. Further refinements of this approach, especially regarding substitutes for islets, could be a promising strategy for improving the outcomes of hepatocyte transplantation.
| S-EPMC8048420 | biostudies-literature
Project description:Induction of hepatocyte senescence is known to inhibit hepatocellular carcinoma (HCC). Until now, it has not been clear how the degree of liver injury dictates hepatocyte senescence and carcinogenesis. In this study, we investigated whether the severity of injury determines cell fate decisions between hepatocyte senescence and carcinogenesis. After testing of different degrees of liver injury, we found that hepatocyte senescence is strongly induced in the setting of severe acute liver injury. Longer-term, moderate liver injury did not result into hepatocyte senescence, but instead led to a significant incidence of HCC. In addition, carcinogenesis was significantly reduced by the induction of severe acute injury after chronic moderate liver injury. We conclude that severe acute liver injury leads to hepatocyte senescence along with a low incidence of HCC, whereas chronic moderate injury allows hepatocytes to proliferate rather than to enter into senescence, and correlates with a high incidence of HCC. This study improves our understanding in hepatocyte cell fate decisions and suggests a potential clinical strategy to induce senescence to treat HCC.
2018-12-20 | GSE108328 | GEO
Project description:Cerebral organoids (COs) in cell replacement therapy offer a viable approach to reconstructing neural circuits for individuals suffering from stroke or traumatic brain injuries. Successful transplantation relies on effective engraftment and neurite extension from the grafts. Earlier research has validated the effectiveness of delaying the transplantation procedure by one week. Here, we hypothesized that brain tissues one week following a traumatic brain injury possess a more favorable environment for cell transplantation when compared to immediately after injury. We performed a transcriptomic comparison to differentiate gene expression between these two temporal states. In controlled in vitro conditions, recombinant human progranulin (rhPGRN) bolstered the survival rate of dissociated neurons sourced from human-induced pluripotent stem cell-derived cerebral organoids (hiPSC-COs) under conditions of enhanced oxidative stress. This increase in viability was attributable to a reduction in apoptosis via Akt phosphorylation. In addition, rhPGRN pretreatment before in vivo transplantation experiments augmented the engraftment efficiency of hiPSC-COs considerably and facilitated neurite elongation along the host brain’s corticospinal tracts. Subsequent histological assessments at three months post-transplantation revealed an elevated presence of graft-derived subcerebral projection neurons—crucial elements for reconstituting neural circuits—in the rhPGRN-treated group. These outcomes highlight the potential of PGRN as a neurotrophic factor suitable for incorporation into hiPSC-CO-based cell therapies.
2024-11-20 | GSE269438 | GEO
Project description:Successful Preclinical Islet Transplantation in the Subcutaneous Space for Type 1 Diabetes
| PRJNA607700 | ENA