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Yap1-Scribble polarization is required for hematopoietic stem cell division and fate.

ABSTRACT: Yap1 and its paralogue Taz largely control epithelial tissue growth. We have identified that hematopoietic stem cell (HSC) fitness response to stress depends on Yap1 and Taz. Deletion of Yap1 and Taz induces a loss of HSC quiescence, symmetric self-renewal ability, and renders HSC more vulnerable to serial myeloablative 5-fluorouracil treatment. This effect depends on the predominant cytosolic polarization of Yap1 through a PDZ domain-mediated interaction with the scaffold Scribble. Scribble and Yap1 coordinate to control cytoplasmic Cdc42 activity and HSC fate determination in vivo. Deletion of Scribble disrupts Yap1 copolarization with Cdc42 and decreases Cdc42 activity, resulting in increased self-renewing HSC with competitive reconstitution advantages. These data suggest that Scribble/Yap1 copolarization is indispensable for Cdc42-dependent activity on HSC asymmetric division and fate. The combined loss of Scribble, Yap1, and Taz results in transcriptional upregulation of Rac-specific guanine nucleotide exchange factors, Rac activation, and HSC fitness restoration. Scribble links Cdc42 and the cytosolic functions of the Hippo signaling cascade in HSC fate determination.

SUBMITTER: Althoff MJ

PROVIDER: S-EPMC7568035 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Yap1-Scribble polarization is required for hematopoietic stem cell division and fate

Project description:Yap1 and its paralogue Taz largely control epithelial tissue growth. We have identified that hematopoietic stem cell (HSC) fitness response to stress depends on Yap1 and Taz. Deletion of Yap1 and Taz induces a loss of HSC quiescence, symmetric self-renewal ability and renders HSC more vulnerable to serial myeloablative 5-fluorouracil treatment. This effect depends on the predominant cytosolic polarization of Yap1 through its PDZ domain-mediated interaction with the scaffold Scribble. Scribble and Yap1 coordinate to control cytoplasmic Cdc42 activity and HSC fate determination in vivo. Deletion of Scribble disrupts Yap1 co-polarization with Cdc42 and decreases Cdc42 activity, resulting in increased selfrenewing HSC with competitive reconstitution advantages. These data suggest that Scribble/Yap1 co-polarization is indispensable for Cdc42- dependent activity on HSC asymmetric division and fate. The combined loss of Scribble, Yap1 and Taz results in transcriptional upregulation of Rac-specific guanine nucleotide exchange factors, Rac activation and HSC fitness restoration. Scribble links Cdc42 and the cytosolic functions of the Hippo signaling cascade in HSC fate determination.

2020-05-30 | GSE151465 | GEO

Yap1-Scribble polarization is required for hematopoietic stem cell division and fate

Project description:Yap1-Scribble polarization is required for hematopoietic stem cell division and fate

| PRJNA635915 | ENA

Abscission Couples Cell Division to Embryonic Stem Cell Fate.

Project description:Cell fate transitions are key to development and homeostasis. It is thus essential to understand the cellular mechanisms controlling fate transitions. Cell division has been implicated in fate decisions in many stem cell types, including neuronal and epithelial progenitors. In other stem cells, such as embryonic stem (ES) cells, the role of division remains unclear. Here, we show that exit from naive pluripotency in mouse ES cells generally occurs after a division. We further show that exit timing is strongly correlated between sister cells, which remain connected by cytoplasmic bridges long after division, and that bridge abscission progressively accelerates as cells exit naive pluripotency. Finally, interfering with abscission impairs naive pluripotency exit, and artificially inducing abscission accelerates it. Altogether, our data indicate that a switch in the division machinery leading to faster abscission regulates pluripotency exit. Our study identifies abscission as a key cellular process coupling cell division to fate transitions.

| S-EPMC7594744 | biostudies-literature

Hematopoietic stem cell fate through metabolic control.

Project description:Hematopoietic stem cells maintain a quiescent state in the bone marrow to preserve their self-renewal capacity, but also undergo cell divisions as required. Organelles such as the mitochondria sustain cumulative damage during these cell divisions and this damage may eventually compromise the cells' self-renewal capacity. Hematopoietic stem cell divisions result in either self-renewal or differentiation, with the balance between the two affecting hematopoietic homeostasis directly; however, the heterogeneity of available hematopoietic stem cell-enriched fractions, together with the technical challenges of observing hematopoietic stem cell behavior, has long hindered the analysis of individual hematopoietic stem cells and prevented the elucidation of this process. Recent advances in genetic models, metabolomics analyses, and single-cell approaches have revealed the contributions made to hematopoietic stem cell self-renewal by metabolic cues, mitochondrial biogenesis, and autophagy/mitophagy, which have highlighted mitochondrial quality control as a key factor in the equilibrium of hematopoietic stem cells. A deeper understanding of precisely how specific modes of metabolism control hematopoietic stem cells fate at the single-cell level is therefore not only of great biological interest, but will also have clear clinical implications for the development of therapies for hematological diseases.

| S-EPMC6084457 | biostudies-literature

FAM122A is required for hematopoietic stem cell function.

Project description: Not available

| S-EPMC8257486 | biostudies-literature

The Effect of Mesenchymal Stem Cell-Derived Extracellular Vesicles on Hematopoietic Stem Cells Fate.

Project description:Hematopoietic stem cells (HSCs) are multipotent stem cells, with self-renewal ability as well as ability to generate all blood cells. Mesenchymal stem cells (MSCs) are multipotent stem cells, with self-renewal ability, and capable of differentiating into a variety of cell types. MSCs have supporting effects on hematopoiesis; through direct intercellular communications as well as secreting cytokines, chemokines, and extracellular vesicles (EVs). Recent investigations demonstrated that some biological functions and effects of MSCs are mediated by their EVs. MSC-EVs are the cell membrane and endosomal membrane compartments, which are important mediators in the intercellular communications. MSC-EVs contain some of the molecules such as proteins, mRNA, siRNA, and miRNA from their parental cells. MSC-EVs are able to inhibit tumor, repair damaged tissue, and modulate immune system responses. MSC-EVs compared to their parental cells, may have the specific safety advantages such as the lower potential to trigger immune system responses and limited side effects. Recently some studies demonstrated the effect of MSC-EVs on the expansion, differentiation, and clinical applications of HSCs such as improvement of hematopoietic stem cell transplantation (HSCT) and inhibition of graft versus host disease (GVHD). HSCT may be the only therapeutic choice for patients who suffer from malignant and non-malignant hematological disorders. However, there are several severe side eﬀects such GVHD that restricts the successfulness of HSCT. In this review, we will discuss the most important effects of MSCs and MSC-EVs on the improvement of HSCT, inhibition and treatment of GVHD, as well as, on the expansion of HSCs.

| S-EPMC5788208 | biostudies-other

AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate.

Project description:Hypercholesterolemia, the driving force of atherosclerosis, accelerates the expansion and mobilization of hematopoietic stem and progenitor cells (HSPCs). The molecular determinants connecting hypercholesterolemia with hematopoiesis are unclear. Here, we report that a somite-derived prohematopoietic cue, AIBP, orchestrates HSPC emergence from the hemogenic endothelium, a type of specialized endothelium manifesting hematopoietic potential. Mechanistically, AIBP-mediated cholesterol efflux activates endothelial Srebp2, the master transcription factor for cholesterol biosynthesis, which in turn transactivates Notch and promotes HSPC emergence. Srebp2 inhibition impairs hypercholesterolemia-induced HSPC expansion. Srebp2 activation and Notch up-regulation are associated with HSPC expansion in hypercholesterolemic human subjects. Genome-wide chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing (RNA-seq), and assay for transposase-accessible chromatin using sequencing (ATAC-seq) indicate that Srebp2 transregulates Notch pathway genes required for hematopoiesis. Our studies outline an AIBP-regulated Srebp2-dependent paradigm for HSPC emergence in development and HPSC expansion in atherosclerotic cardiovascular disease.

| S-EPMC6469354 | biostudies-literature

The fate of human Langerhans cells in hematopoietic stem cell transplantation.

Project description:Langerhans cells (LC) and other antigen-presenting cells are believed to be critical in initiating graft versus host responses that influence the outcome of allogeneic hematopoietic stem cell transplantation. However, their fate in humans is poorly understood. We have sought to define the effect of conditioning regimes and graft versus host disease (GVHD) on the survival of recipient LC and reconstitution of donor cells after transplant. Confocal microscopy of epidermal sheets shows that full intensity transplant (FIT) depletes LC more rapidly than reduced intensity transplant (RIT) at day 0, although the nadir is similar in both at 14-21 d. Recovery occurs rapidly within 40 d in the absence of acute GVHD, but is delayed beyond 100 d when GVHD is active. LC chimerism was determined in sex-mismatched transplants using a two-step Giemsa/fluorescence in situ hybridization assay on isolated cells. Acquisition of donor chimerism at 40 d is more rapid after FIT (97%) than RIT (36.5%), irrespective of blood myeloid engraftment. At 100 d, all transplants achieve at least 90% LC donor chimerism and over half achieve 100%. Complete donor chimerism is associated with prior acute cutaneous GVHD, suggesting a role for allogeneic T cells in promoting LC engraftment.

| S-EPMC2118090 | biostudies-literature

aPKC? controls epidermal homeostasis and stem cell fate through regulation of division orientation.

Project description:The atypical protein kinase C (aPKC) is a key regulator of polarity and cell fate in lower organisms. However, whether mammalian aPKCs control stem cells and fate in vivo is not known. Here we show that loss of aPKC? in a self-renewing epithelium, the epidermis, disturbed tissue homeostasis, differentiation, and stem cell dynamics, causing progressive changes in this tissue. This was accompanied by a gradual loss of quiescent hair follicle bulge stem cells and a temporary increase in proliferating progenitors. Lineage tracing analysis showed that loss of aPKC? altered the fate of lower bulge/hair germ stem cells. This ultimately led to loss of proliferative potential, stem cell exhaustion, alopecia, and premature aging. Inactivation of aPKC? produced more asymmetric divisions in different compartments, including the bulge. Thus, aPKC? is crucial for homeostasis of self-renewing stratifying epithelia, and for the regulation of cell fate, differentiation, and maintenance of epidermal bulge stem cells likely through its role in balancing symmetric and asymmetric division.

| S-EPMC3776350 | biostudies-literature

Ca<sup>2+</sup>-mitochondria axis drives cell division in hematopoietic stem cells.

Project description:Most of the hematopoietic stem cells (HSCs) within the bone marrow (BM) show quiescent state with a low mitochondrial membrane potential (ΔΨm). In contrast, upon stress hematopoiesis, HSCs actively start to divide. However, the underlying mechanism for the initiation of HSC division still remains unclear. To elucidate the mechanism underlying the transition of cell cycle state in HSCs, we analyzed the change of mitochondria in HSCs after BM suppression induced by 5-fluoruracil (5-FU). We found that HSCs initiate cell division after exhibiting enhanced ΔΨm as a result of increased intracellular Ca2+ level. Although further activation of Ca2+-mitochondria pathway led to loss of HSCs after cell division, the appropriate suppression of intracellular Ca2+ level by exogenous adenosine or Nifedipine, a Ca2+ channel blocker, prolonged cell division interval in HSCs, and simultaneously achieved both cell division and HSC maintenance. Collectively, our results indicate that the Ca2+-mitochondria pathway induces HSC division critically to determine HSC cell fate.

| S-EPMC6080917 | biostudies-literature

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