Pollardmacias9956

Ionizing radiation exposure results in acute and delayed bone marrow suppression. Treatment of mice with 16,16-dimethyl prostaglandin E2 (dmPGE2) prior to lethal ionizing radiation (IR) facilitates survival, but the cellular and molecular mechanisms are unclear. In this study we show that dmPGE2 attenuates loss and enhances recovery of bone marrow cellularity, corresponding to a less severe hematopoietic stem cell nadir, and significantly preserves long-term repopulation capacity and progenitor cell function. Mechanistically, dmPGE2 suppressed hematopoietic stem cell (HSC) proliferation through 24 h post IR, which correlated with fewer DNA double-strand breaks and attenuation of apoptosis, mitochondrial compromise, oxidative stress, and senescence. RNA sequencing of HSCs at 1 h and 24 h post IR identified a predominant interference with IR-induced p53-downstream gene expression at 1 h, and confirmed the suppression of IR-induced cell-cycle genes at 24 h. These data identify mechanisms of dmPGE2 radioprotection and its potential role as a medical countermeasure against radiation exposure.The systemic amyloidoses are diverse disorders in which misfolded proteins are secreted by effector organs and deposited as proteotoxic aggregates at downstream tissues. Although well described clinically, the contribution of synthesizing organs to amyloid disease pathogenesis is unknown. Here, we utilize hereditary transthyretin amyloidosis (ATTR amyloidosis) induced pluripotent stem cells (iPSCs) to define the contribution of hepatocyte-like cells (HLCs) to the proteotoxicity of secreted transthyretin (TTR). To this end, we generated isogenic, patient-specific iPSCs expressing either amyloidogenic or wild-type TTR. We combined this tool with single-cell RNA sequencing to identify hepatic proteostasis factors correlating with destabilized TTR production in iPSC-derived HLCs. By generating an ATF6 inducible patient-specific iPSC line, we demonstrated that enhancing hepatic ER proteostasis preferentially reduces the secretion of amyloidogenic TTR. These data highlight the liver's capacity to chaperone misfolded TTR prior to deposition, and moreover suggest the potential for unfolded protein response modulating therapeutics in the treatment of diverse systemic amyloidoses.The primary cilium is the non-motile cilium present in most mammalian cell types and functions as an antenna for cells to sense signals. Ablating primary cilia in postnatal newborn neurons of the dentate gyrus (DG) results in both reduced dendritic arborization and synaptic strength, leading to hippocampal-dependent learning and memory deficits. Fragile X syndrome (FXS) is a common form of inheritance for intellectual disabilities with a high risk for autism spectrum disorders, and Fmr1 KO mice, a mouse model for FXS, demonstrate deficits in newborn neuron differentiation, dendritic morphology, and memory formation in the DG. Here, we found that the number of primary cilia in Fmr1 KO mice is reduced, specifically in the DG of the hippocampus. Moreover, this cilia loss was observed postnatally mainly in newborn neurons generated from the DG, implicating that these primary ciliary deficits may possibly contribute to the pathophysiology of FXS.Characterized by the expansion of somatic mutations in the hematopoietic lineages of aging individuals, clonal hematopoiesis of indeterminate potential (CHIP) is a common condition that increases the risk of developing hematological malignancies and cardiovascular disease (CVD). The presence of CHIP-associated mutations in hematopoietic stem and progenitor cells (HSPCs) suggests that these mutations may alter the functions of the diverse hematopoietic lineages, many of which influence the pathogenesis of CVD. Inflammation may be a potential pathogenic mechanism, linking both CVD and hematological malignancy. However, it remains unknown whether CHIP-associated CVD and hematological malignancy are features of a common disease spectrum. The contributions of CHIP-associated mutations to both CVD and hematological malignancy underscore the importance of stem cell biology in pathogenesis and treatment. This review discusses possible mechanisms underlying the contributions of multiple hematopoietic lineages to CHIP-associated CVD and the putative pathogenic links between CHIP-associated CVD and hematological malignancy.Recent studies have demonstrated that fibroblasts can be directly converted into functional Leydig cells by transcription factors. However, the transgenic approach used in these studies raises safety concerns for its future application. Here, we report that fibroblasts can be directly reprogrammed into Leydig-like cells by exposure to a combination of forskolin, 20α-hydroxycholesterol, luteinizing hormone, and SB431542. These chemical compound-induced Leydig-like cells (CiLCs) express steroidogenic genes and have a global gene expression profile similar to that of progenitor Leydig cells, although not identical. selleck kinase inhibitor In addition, these cells can survive in testis and produce testosterone in a circadian rhythm. This induction strategy is applicable to reprogramming human periodontal ligament fibroblasts toward Leydig-like cells. These findings demonstrated fibroblasts can be directly converted into Leydig-like cells by pure chemical compounds. This strategy overcomes the limitations of conventional transgenic-based reprogramming and provides a simple, effective approach for Leydig cell-based therapy while simultaneously preserving the hypothalamic-pituitary-gonadal axis.We earlier showed that outside-in integrin signaling through POSTN-ITGAV interaction plays an important role in regulating adult hematopoietic stem cell (HSC) quiescence. Here, we show that Itgav deletion results in increased frequency of phenotypic HSCs in fetal liver (FL) due to faster proliferation. Systemic deletion of Postn led to increased proliferation of FL HSCs, albeit without any loss of stemness, unlike Vav-Itgav-/- HSCs. Based on RNA sequencing analysis of FL and bone marrow HSCs, we predicted the involvement of DNA damage response pathways in this dichotomy. Indeed, proliferative HSCs from Postn-deficient FL tissues showed increased levels of DNA repair, resulting in lesser double-strand breaks. Thus POSTN, with its expression majorly localized in the vascular endothelium of FL tissue, acts as a regulator of stem cell pool size during development. Overall, we demonstrate that the duality of response to proliferation in HSCs is developmental stage dependent and can be correlated with DNA damage responses.