Asymmetric segregation and self-renewal of hematopoietic stem and progenitor cells with endocytic Ap2a2
ABSTRACT The stem cell-intrinsic model of self-renewal via asymmetric cell division (ACD) posits that fate determinants be partitioned unequally between daughter cells to either activate or suppress the stemness state. ACD is a purported mechanism by which hematopoietic stem cells (HSCs) self-renew, but definitive evidence for this cellular process remains open to conjecture. To address this issue, we chose 73 candidate genes that function within the cell polarity network to identify potential determinants that may concomitantly alter HSC fate while also exhibiting asymmetric segregation at cell division. Initial gene-expression profiles of polarity candidates showed high and differential expression in both HSCs and leukemia stem cells. Altered HSC fate was assessed by our established in vitro to in vivo screen on a subcohort of candidate polarity genes, which revealed 6 novel positive regulators of HSC function: Ap2a2, Gpsm2, Tmod1, Kif3a, Racgap1, and Ccnb1. Interestingly, live-cell videomicroscopy of the endocytic protein AP2A2 shows instances of asymmetric segregation during HSC/progenitor cell cytokinesis. These results contribute further evidence that ACD is functional in HSC self-renewal, suggest a role for Ap2a2 in HSC activity, and provide a unique opportunity to prospectively analyze progeny from HSC asymmetric divisions.
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ABSTRACT: Recent studies have significantly improved our understanding of the role microRNAs (miRNAs) play in regulating normal hematopoiesis. miRNAs are critical for maintaining hematopoietic stem cell function and the development of mature progeny. Thus, perhaps it is not surprising that miRNAs serve as oncogenes and tumor suppressors in hematologic malignancies arising from hematopoietic stem and progenitor cells, such as the myeloid disorders. A number of studies have extensively documented the widespread dysregulation of miRNA expression in human acute myeloid leukemia (AML), inspiring numerous explorations of the functional role of miRNAs in myeloid leukemogenesis. While these investigations have confirmed that a large number of miRNAs exhibit altered expression in AML, only a small fraction has been confirmed as functional mediators of AML development or maintenance. Herein, we summarize the miRNAs for which strong experimental evidence supports their functional roles in AML pathogenesis. We also discuss the implications of these studies on the development of miRNA-directed therapies in AML.Frontiers in Genetics 11/2014; 5:361. DOI:10.3389/fgene.2014.00361
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ABSTRACT: A growing number of studies are revealing that cells reorganize their cytoskeleton when exposed to conditions of microgravity. Most, if not all, of the structural changes observed on flown cells can be explained by modulation of RhoGTPases, which are mechanosensitive switches responsible for cytoskeletal dynamics control. This review identifies general principles defining cell sensitivity to gravitational stresses. We discuss what is known about changes in cell shape, nucleus, and focal adhesions and try to establish the relationship with specific RhoGTPase activities. We conclude by considering the potential relevance of live imaging of RhoGTPase activity or cytoskeletal structures in order to enhance our understanding of cell adaptation to microgravity-related conditions.BioMed Research International 09/2014; DOI:10.1155/2015/747693 · 2.71 Impact Factor
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ABSTRACT: A hypomorphic Prep1 mutation results in embryonic lethality at late gestation with a pleiotropic embryonic phenotype that includes defects in all hematopoietic lineages. Reduced functionality of the hematopoietic stem cells (HSCs) compartment might be responsible for the hematopoietic phenotype observed at mid-gestation. In this paper we demonstrate that Prep1 regulates the number of HSCs in fetal livers (FLs), their clonogenic potential and their ability to de novo generate the hematopoietic system in ablated hosts. Furthermore, we show that Prep1 controls the self-renewal ability of the FL HSC compartment as demonstrated by serial transplantation experiments. The premature exhaustion of Prep1 mutant HSCs correlates with the reduced quiescent stem cell pool thus suggesting that Prep1 regulates the self-renewal ability by controlling the quiescence/proliferation balance. Finally, we show that in FL HSCs Prep1 absence induces the interferon signaling pathway leading to premature cycling and exhaustion of fetal HSCs.PLoS ONE 09/2014; 9(9):e107916. DOI:10.1371/journal.pone.0107916 · 3.53 Impact Factor