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Ex-vivo Human Hematopoietic Stem Cell Expansion Requires Coordination of Cellular Reprogramming with Mitochondrial Remodeling and P53 Activation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE110974 | GEO | 2018/10/10

REPOSITORIES: GEO

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Ex vivo human HSC expansion requires coordination of cellular reprogramming with mitochondrial remodeling and p53 activation.

Project description:The limited number of hematopoietic stem cells (HSCs) in umbilical cord blood (UCB) units restricts their use for stem cell transplantation. Ex vivo treatment of UCB-CD34+ cells with valproic acid (VPA) increases the number of transplantable HSCs. In this study, we demonstrate that HSC expansion is not merely a result of proliferation of the existing stem cells but, rather, a result of a rapid reprogramming of CD34+CD90- cells into CD34+CD90+ cells, which is accompanied by limited numbers of cell divisions. Beyond this phenotypic switch, the treated cells acquire and retain a transcriptomic and mitochondrial profile, reminiscent of primary HSCs. Single and bulk RNA-seq revealed a signature highly enriched for transcripts characteristic of primary HSCs. The acquisition of this HSC signature is linked to mitochondrial remodeling accompanied by a reduced activity and enhanced glycolytic potential. These events act in concert with a modest upregulation of p53 activity to limit the levels of reactive oxygen species (ROS). Inhibition of either glycolysis or p53 activity impairs HSC expansion. This study indicates that a complex interplay of events is required for effective ex vivo expansion of UCB-HSCs.

| S-EPMC6199653 | biostudies-literature

Ex-vivo Human Hematopoietic Stem Cell Expansion Requires Coordination of Cellular Reprogramming with Mitochondrial Remodeling and P53 Activation [bulk]

Project description:Ex-vivo culture conditions used to expand the numbers of hematopoietic stem cells (HSCs) present within an umbilical cord blood (UCB) unit create cellular stresses leading to loss or at best maintenance of the primitive HSCs. Recently, we have shown that treatment with a histone deacetylase inhibitor, valproic acid (VPA), increases substantially the numbers of transplantable HSCs from UCB-CD34+ cells. In this report, we demonstrate that VPA treatment orchestrates cellular mechanisms that drive UCB-CD34+ cells into a primitive state in which they acquire and retain phenotypic, transcriptomic and primitive mitochondrial profiles, all of which characterize long-term HSCs. Remarkably, our data link the acquisition of the HSC phenotype to the remodeling of the mitochondrial network and p53 activation and establish both as critical regulators of ROS and therefore of HSC fate. VPA treatment leads to restructured mitochondria with reduced mass, membrane potential and ROS levels. p53 activity is critical for the activation of antioxidant defense mechanisms, which rely on magnesium superoxide dismutase (MnSOD) activity. Failure to activate the p53-MnSOD axis compromises both the acquisition and the maintenance of the HSC phenotype. These studies indicate that suppression of ROS through the coordination of p53 activity and mitochondrial remodeling determines the fate of ex-vivo expanded human HSCs

2018-10-10 | GSE110968 | GEO

Ex-vivo Human Hematopoietic Stem Cell Expansion Requires Coordination of Cellular Reprogramming with Mitochondrial Remodeling and P53 Activation[10x]

2018-10-10 | GSE110973 | GEO

Ex-vivo Human Hematopoietic Stem Cell Expansion Requires Coordination of Cellular Reprogramming with Mitochondrial Remodeling and P53 Activation

Project description:Ex-vivo Human Hematopoietic Stem Cell Expansion Requires Coordination of Cellular Reprogramming with Mitochondrial Remodeling and P53 Activation

| PRJNA435435 | ENA

Ex-vivo Human Hematopoietic Stem Cell Expansion Requires Coordination of Cellular Reprogramming with Mitochondrial Remodeling and P53 Activation [bulk]

Project description:Ex-vivo Human Hematopoietic Stem Cell Expansion Requires Coordination of Cellular Reprogramming with Mitochondrial Remodeling and P53 Activation [bulk]

| PRJNA435431 | ENA

Ex-vivo Human Hematopoietic Stem Cell Expansion Requires Coordination of Cellular Reprogramming with Mitochondrial Remodeling and P53 Activation[10x]

Project description:Ex-vivo Human Hematopoietic Stem Cell Expansion Requires Coordination of Cellular Reprogramming with Mitochondrial Remodeling and P53 Activation[10x]

| PRJNA435434 | ENA

ADGRG1 enriches for functional human hematopoietic stem cells following ex vivo expansion-induced mitochondrial oxidative stress.

Project description:The heterogeneity of human hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) under stress conditions such as ex vivo expansion is poorly understood. Here, we report that the frequencies of SCID-repopulating cells were greatly decreased in cord blood (CB) CD34+ HSCs and HPCs upon ex vivo culturing. Transcriptomic analysis and metabolic profiling demonstrated that mitochondrial oxidative stress of human CB HSCs and HPCs notably increased, along with loss of stemness. Limiting dilution analysis revealed that functional human HSCs were enriched in cell populations with low levels of mitochondrial ROS (mitoROS) during ex vivo culturing. Using single-cell RNA-Seq analysis of the mitoROS low cell population, we demonstrated that functional HSCs were substantially enriched in the adhesion GPCR G1-positive (ADGRG1+) population of CD34+CD133+ CB cells upon ex vivo expansion stress. Gene set enrichment analysis revealed that HSC signature genes including MSI2 and MLLT3 were enriched in CD34+CD133+ADGRG1+ CB HSCs. Our study reveals that ADGRG1 enriches for functional human HSCs under oxidative stress during ex vivo culturing, which can be a reliable target for drug screening of agonists of HSC expansion.

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Long-term ex vivo expansion of mouse hematopoietic stem cells.

Project description:Utilizing multipotent and self-renewing capabilities, hematopoietic stem cells (HSCs) can maintain hematopoiesis throughout life. However, the mechanism behind such remarkable abilities remains undiscovered, at least in part because of the paucity of HSCs and the modest ex vivo expansion of HSCs in media that contain poorly defined albumin supplements such as bovine serum albumin. Here, we describe a simple platform for the expansion of functional mouse HSCs ex vivo for >1 month under fully defined albumin-free conditions. The culture system affords 236- to 899-fold expansion over the course of a month and is also amenable to clonal analysis of HSC heterogeneity. The large numbers of expanded HSCs enable HSC transplantation into nonconditioned recipients, which is otherwise not routinely feasible because of the large numbers of HSCs required. This protocol therefore provides a powerful approach with which to interrogate HSC self-renewal and lineage commitment and, more broadly, to study and characterize the hematopoietic and immune systems.

| S-EPMC7206416 | biostudies-literature

Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells.

Project description:Successful ex vivo expansion of hematopoietic stem cells (HSCs) would greatly benefit the treatment of disease and the understanding of crucial questions of stem cell biology. Here we show, using microarray studies, that the HSC-supportive mouse fetal liver CD3(+) cells specifically express the proteins angiopoietin-like 2 (Angptl2) and angiopoietin-like 3 (Angptl3). We observed a 24- or 30-fold net expansion of long-term HSCs by reconstitution analysis when we cultured highly enriched HSCs for 10 days in the presence of Angptl2 or Angptl3 together with saturating levels of other growth factors. The coiled-coil domain of Angptl2 was capable of stimulating expansion of HSCs. Furthermore, angiopoietin-like 5, angiopoietin-like 7 and microfibril-associated glycoprotein 4 also supported expansion of HSCs in culture.

| S-EPMC2771412 | biostudies-literature

Mitochondrial metabolism in hematopoietic stem cells requires functional FOXO3.

Project description:Hematopoietic stem cells (HSC) are primarily dormant but have the potential to become highly active on demand to reconstitute blood. This requires a swift metabolic switch from glycolysis to mitochondrial oxidative phosphorylation. Maintenance of low levels of reactive oxygen species (ROS), a by-product of mitochondrial metabolism, is also necessary for sustaining HSC dormancy. Little is known about mechanisms that integrate energy metabolism with hematopoietic stem cell homeostasis. Here, we identify the transcription factor FOXO3 as a new regulator of metabolic adaptation of HSC. ROS are elevated in Foxo3(-/-) HSC that are defective in their activity. We show that Foxo3(-/-) HSC are impaired in mitochondrial metabolism independent of ROS levels. These defects are associated with altered expression of mitochondrial/metabolic genes in Foxo3(-/-) hematopoietic stem and progenitor cells (HSPC). We further show that defects of Foxo3(-/-) HSC long-term repopulation activity are independent of ROS or mTOR signaling. Our results point to FOXO3 as a potential node that couples mitochondrial metabolism with HSC homeostasis. These findings have critical implications for mechanisms that promote malignant transformation and aging of blood stem and progenitor cells.

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