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:Animals possess control mechanisms to synchronize organ and organismal size during growth, to maintain tissue integrity through homeostatic cell proliferation, and to counter major injury with regeneration. A principal research goal is to elucidate mitogenic triggers that underlie these mechanisms. Here, from a large-scale in vivo chemical screen, we discovered that analogues of the essential nutrient vitamin D potently activate heart muscle cell division in larval zebrafish. Unexpectedly, loss- and gain-of-function methods to modulate vitamin D signaling altered metabolic and cell cycle gene expression in zebrafish larvae and dictated rates of organismal growth. Systemic vitamin D treatment sharply increased in vivo cell proliferation in a variety of adult cell types including cardiomyocytes, hepatocytes, osteoblasts, cardiac mesothelium, skin and corneal epithelium, and retina, and enhanced injury-induced heart and appendage regeneration. Our experiments identify vitamin D signaling as a broad growth- and regeneration-initiating influence throughout the life stages of a vertebrate model system.