Project description:We assess the difference in overall gene expression levels post 2/3 hepatectomy in mouse livers as a result of loss of integrin αvβ8, through microArray experiments. We hypothesized that depletion of hepatocyte integrin αvβ8 would increase hepatocyte proliferation and accelerate liver regeneration following injury. Through use of microarray experiments we identify genes that are up/down regulated only in the mice with integrin αvβ8 depletion.
Project description:The peripheral nervous system (PNS) regenerates after injury. However regeneration is often compromised in case of large lesions, the speed of axon reconnection to their target being critical for successful functional recovery. After injury, mature Schwann cells (SCs) convert into repair cells that foster axonal regrowth, and redifferentiate to rebuild myelin. These processes require the regulation of several transcription factors, but the driving mechanisms remain partially understood. Here, we identify an early response to injury controlled by histone deacetylase (HDAC)2, which coordinates the action of other chromatin-remodeling enzymes to induce the upregulation of Oct6, a key transcription factor for Schwann cell development. Inactivating this mechanism using mouse genetics allows earlier conversion into repair cells and leads to faster axonal regrowth, but impairs remyelination. Consistently, short-term HDAC1/2 inhibitor treatment early after lesion accelerates functional recovery and enhances regeneration, thereby identifying a new therapeutic strategy to improve PNS regeneration after lesion.
Project description:Adult liver has enormous regenerative capacity as it can regenerate after losing two-thirds of its mass while sustaining essential metabolic functions. How the liver balances dual demands for increased proliferative activity with maintenance of organ function is unknown, but essential to prevent liver failure. Using partial hepatectomy (PHx) in mice to model liver regeneration, we integrated single-cell RNA and ATAC sequencing to map state transitions in ~ 13,000 hepatocytes at single-cell resolution as livers regenerated, and validated key findings with immunohistochemistry, to uncover how the organ regenerates hepatocytes while simultaneously fulfilling its vital tissue-specific functions. After PHx, hepatocytes rapidly and transiently diversified into multiple distinct populations with distinct functional bifurcation: some retained the chromatin landscapes and transcriptomes of hepatocytes in undamaged adult livers while others transitioned to acquire chromatin landscapes and transcriptomes of fetal hepatocytes. Injury-related signaling pathways known to be critical for regeneration were activated in transitioning hepatocytes and the most fetal-like hepatocytes exhibited chromatin landscapes that were enriched with transcription factors regulated by those pathways.
Project description:Adult liver has enormous regenerative capacity as it can regenerate after losing two-thirds of its mass while sustaining essential metabolic functions. How the liver balances dual demands for increased proliferative activity with maintenance of organ function is unknown, but essential to prevent liver failure. Using partial hepatectomy (PHx) in mice to model liver regeneration, we integrated single-cell RNA and ATAC sequencing to map state transitions in ~ 13,000 hepatocytes at single-cell resolution as livers regenerated, and validated key findings with immunohistochemistry, to uncover how the organ regenerates hepatocytes while simultaneously fulfilling its vital tissue-specific functions. After PHx, hepatocytes rapidly and transiently diversified into multiple distinct populations with distinct functional bifurcation: some retained the chromatin landscapes and transcriptomes of hepatocytes in undamaged adult livers while others transitioned to acquire chromatin landscapes and transcriptomes of fetal hepatocytes. Injury-related signaling pathways known to be critical for regeneration were activated in transitioning hepatocytes and the most fetal-like hepatocytes exhibited chromatin landscapes that were enriched with transcription factors regulated by those pathways.
Project description:Adult liver has enormous regenerative capacity as it can regenerate after losing two-thirds of its mass while sustaining essential metabolic functions. How the liver balances dual demands for increased proliferative activity with maintenance of organ function is unknown, but essential to prevent liver failure. Using partial hepatectomy (PHx) in mice to model liver regeneration, we integrated single-cell RNA and ATAC sequencing to map state transitions in ~ 13,000 hepatocytes at single-cell resolution as livers regenerated, and validated key findings with immunohistochemistry, to uncover how the organ regenerates hepatocytes while simultaneously fulfilling its vital tissue-specific functions. After PHx, hepatocytes rapidly and transiently diversified into multiple distinct populations with distinct functional bifurcation: some retained the chromatin landscapes and transcriptomes of hepatocytes in undamaged adult livers while others transitioned to acquire chromatin landscapes and transcriptomes of fetal hepatocytes. Injury-related signaling pathways known to be critical for regeneration were activated in transitioning hepatocytes and the most fetal-like hepatocytes exhibited chromatin landscapes that were enriched with transcription factors regulated by those pathways.
Project description:Adult liver has enormous regenerative capacity as it can regenerate after losing two-thirds of its mass while sustaining essential metabolic functions. How the liver balances dual demands for increased proliferative activity with maintenance of organ function is unknown, but essential to prevent liver failure. Using partial hepatectomy (PHx) in mice to model liver regeneration, we integrated single-cell RNA and ATAC sequencing to map state transitions in ~ 13,000 hepatocytes at single-cell resolution as livers regenerated, and validated key findings with immunohistochemistry, to uncover how the organ regenerates hepatocytes while simultaneously fulfilling its vital tissue-specific functions. After PHx, hepatocytes rapidly and transiently diversified into multiple distinct populations with distinct functional bifurcation: some retained the chromatin landscapes and transcriptomes of hepatocytes in undamaged adult livers while others transitioned to acquire chromatin landscapes and transcriptomes of fetal hepatocytes. Injury-related signaling pathways known to be critical for regeneration were activated in transitioning hepatocytes and the most fetal-like hepatocytes exhibited chromatin landscapes that were enriched with transcription factors regulated by those pathways.
Project description:The liver has a remarkable capacity to regenerate, which is sustained by the ability of hepatocytes to act as facultative stem cells that, while normally quiescent, re-enter the cell cycle upon injury. In rodents, growth factor signaling is indispensable, whereas Wnt/β-catenin is not required for effective tissue repair. However, molecular networks controlling human liver regeneration remain unclear.