Enterocyte dedifferentiation drives colonic regeneration following irradiation injury [scRNA-seq]
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PROVIDER: PRJNA1148083 | ENA |
REPOSITORIES: ENA
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Project description:The intestinal epithelium consistently exposes to various injuries and exhibits remarkable regenerative capacity. Although small intestinal regeneration has been extensively investigated, the mechanisms governing colonic regeneration remain poorly understood. Here, we identify irradiation-induced regenerative cells (IRECs), a previously unrecognized colonic enterocyte population, emerges following irradiation injury. IRECs, marked by the gene YuanShangCao (Ysc), undergo dedifferentiation and transition into a stem-like state, contributing to epithelial regeneration. IREC ablation severely impairs colonic repair. Mechanistically, YSC promotes colonic regeneration by preventing the lysosomal degradation of YAP. Furthermore, we demonstrate a critical role of p53 in colonic regeneration by inducing Ysc expression. Together, our findings define IRECs as an irradiation injury-induced enterocyte population that dedifferentiate into stem cells in colon epithelial repair and establish the p53-YSC-YAP axis plays a key role in this process, deepening the understanding of colonic diseases.
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Project description:Mammalian tissues have a limited regenerative capacity. Previous studies showed that dedifferentiation contributes to tissue regeneration in non-mammalian vertebrate species such as zebrafish and newt. However, dedifferentiation is rarely observed in mammalian tissues even in the neonatal stage and therefore artificial induction of dedifferentiation might enhance regeneration in mammalian tissues. Here we demonstrate that short-term expression of Yamanaka 4 factors (4F) induces dedifferentiation and proliferation in the liver by using lineage-traceable, hepatocyte-specific 4F inducible mouse model. Global transcriptome analysis shows that 4F expression transiently reduces the expression of hepatic-lineage markers and induces the expression of a large set of proliferative markers and epigenetic modifiers along with global epigenetic changes as assessed by DNA-accessibility analysis. More importantly, lineage-tracing experiments showed that 4F-expressing hepatocytes acquire liver stem/progenitor cell markers, suggesting that 4F induces partial reprogramming. Moreover, 4F enhances MyoD-mediated transdifferentiation in the liver, suggesting that 4F endows hepatocytes with plasticity. Lastly, 4F expression attenuated liver injury associated with more proliferative capacity and better survival rate, indicating that 4F enhances liver regeneration. Taken together, these results demonstrate that liver-specific 4F expression induces dedifferentiation and promotes liver regeneration.
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Project description:Fibroblast Dedifferentiation as a Determinant of Successful Regeneration
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Project description:Cardiac regeneration involves interplay of complex interactions between many different cell types, including cardiomyocytes. The exact mechanism that enables cardiomyocytes to undergo dedifferentiation and proliferation to replace lost cells has been under intense study. Here we report single nuclear RNA sequencing profile of the injured zebrafish heart and identified distinct cardiomyocyte populations in the injured heart. These cardiomyocyte populations indicate diverse functions that includes stress-response, myofibril assembly, proliferation and contraction. The contracting cardiomyocyte population also involves activation of maturation pathways as an early response to injury. This intriguing finding suggests that constant maintenance of distinctive terminally differentiated cardiomyocyte population is important for cardiac function during regeneration. To test this, we determined that cited4a, a p300/CBP transcriptional co-activator, is induced after injury in mature cardiomyocyte population. Moreover, loss-of-cited4a mutants showed increased dedifferentiation, proliferation and accelerated heart regeneration. Thus, suppressing cardiomyocyte maturation pathway activity in injured hearts could be an approach to promote heart regeneration.
2025-01-31 | GSE279845 | GEO
Project description:In vivo reprogramming drives dedifferentiation and enhances liver regeneration
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Project description:Cardiac regeneration involves interplay of complex interactions between many different cell types, including cardiomyocytes. The exact mechanism that enables cardiomyocytes to undergo dedifferentiation and proliferation to replace lost cells has been under intense study. Here we report single nuclear RNA sequencing profile of the injured zebrafish heart and identified distinct cardiomyocyte populations in the injured heart. These cardiomyocyte populations indicate diverse functions that includes stress-response, myofibril assembly, proliferation and contraction. The contracting cardiomyocyte population also involves activation of maturation pathways as an early response to injury. This intriguing finding suggests that constant maintenance of distinctive terminally differentiated cardiomyocyte population is important for cardiac function during regeneration. To test this, we determined that cited4a, a p300/CBP transcriptional co-activator, is induced after injury in mature cardiomyocyte population. Moreover, loss-of-cited4a mutants showed increased dedifferentiation, proliferation and accelerated heart regeneration. Thus, suppressing cardiomyocyte maturation pathway activity in injured hearts could be an approach to promote heart regeneration.
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Project description:We identify arachidonic acid (AA), as a direct proliferation promoter of intestinal epithelial cells, facilitating small intestinal regeneration. In the transcriptomes, it shows that AA treatment upregulated proliferation-related genes including Wnt signaling target genes, while downregulated differentiation-related genes including enterocyte, goblet cell, Paneth cell, enteroendocrine cell, and tuft cell markers. Additionally, AA could also upregulate stem cell-associated genes which have been highly expressed three days after 12Gy IR injury (e.g. Clu, Lamc2, Anxa1, Areg, and Ly6d). The study shows that AA treatment can be considered a potential therapy for irradiation injury repair and tissue regeneration.
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Project description:Limb regeneration, while observed lifelong in salamanders, is restricted to pre-metamorphic stages in Xenopus laevis frogs. After amputation, post-metamorphic frogs form a blastema that grows only an unsegmented cartilage rod. Whether this loss is due to systemic factors such as the immune system or due to an intrinsic incapability of cells to form competent stem cells has been unclear. Here, we use genetic fate mapping to establish that, as in axolotl, connective tissue (CT) cells form the post-metamorphic frog blastema. Using heterochronic transplantation into the limb bud and single-cell transcriptomic profiling, we show that axolotl CT cells fully dedifferentiate and integrate to form lineages including cartilage in the developing limb. In contrast, frog blastema CT cells do not fully re-express the limb bud progenitor program, even when transplanted into the limb bud. Correspondingly, transplanted cells contribute to extraskeletal CT but not to developing cartilage. Further, using single-cell RNA-seq analysis we find that the embryonic and the adult frog cartilage differentiation programs are molecularly distinct. This work defines intrinsic restrictions in CT dedifferentiation as a limitation in adult regeneration.
2021-05-24 | GSE165901 | GEO
Project description:Transcriptional profiling of microscopically laser dissected murine colonic tissue from 3 separate normal crypts, wound associated epithelium (WAE), normal epithelium, and regenerating crypts (day 6 only) at days 2,4,and 6 after colonic mucosal injury. Injury model performed as described in: H. Seno et al., Efficient colonic mucosal wound repair requires Trem2 signaling. Proc. Natl. Acad. Sci. USA 106, 256-261 (2009)
2012-06-18 | E-MTAB-1175 | biostudies-arrayexpress
Project description:cited4a limits CM dedifferentiation and proliferation during zebrafish heart regeneration [snRNA-seq]
| PRJNA1174776 | ENA