Vascular Regulation of Hematopoietic Stem Cell Homeostasis, Regeneration, and Aging

Abstract

Purpose of Review Hematopoietic stem cells (HSCs) sit at the top of the hierarchy that meets the daily burden of blood production. HSC maintenance relies on extrinsic cues from the bone marrow (BM) microenvironment to balance stem cell self-renewal and cell fate decisions. In this brief review, we will highlight the studies and model systems that define the centralized role of BM vascular endothelium in modulating HSC activity in health and stress. Recent Findings The BM microenvironment is composed of a diverse array of intimately associated vascular and perivascular cell types. Recent dynamic imaging studies, coupled with single-cell RNA sequencing (scRNA-seq) and functional readouts, have advanced our understanding of the HSC-supportive cell types and their cooperative mechanisms that govern stem cell fate during homeostasis, regeneration, and aging. These findings have established complex and discrete vascular microenvironments within the BM that express overlapping and unique paracrine signals that modulate HSC fate. Summary Understanding the spatial and reciprocal HSC-niche interactions and the molecular mechanisms that govern HSC activity in the BM vascular microenvironment will be integral in developing therapies aimed at ameliorating hematological disease and supporting healthy hematopoietic output.

Integration of single-cell transcriptomes and biological function reveals distinct behavioral patterns in bone marrow endothelium

“…A critical function of ECs in the BM is to support HSCs in the vascular stem cell niche 3 , 33 . This method provided the opportunity to compare the ability of Emcn + and Emcn − BMECs to sustain hematopoietic stem/progenitor cells (HSPC: lineage − Sca-1 + cKit + , LSK) in vitro.…”

“…In the BM, EC are a critical component of the hematopoietic stem cell (HSC) niche 6 , 33 , 39 , 40 . Attempts to recapitulate the interactions between BMECs and HSCs in vitro, particularly in mouse, have been challenged by the difficulty to isolate and maintain BMECs in vitro.…”

Engineering strategies to achieve efficientin vitroexpansion of haematopoietic stem cells: development and improvement

“…28 This perivascular location near the endosteum is called the vascular niche. 29 In the vascular niche, stromal cells and endothelial cells surround HSCs and their progeny forming a protective environment and maintaining the HSC population by secreting CXCL12, stem cell factor (SCF, also known as KITL) and probably other cytokines. 23,30,31 Among these support cells, a particular type of perivascular stromal cell can secrete a large amount of CXCL12 and contact HSCs directly, CXCL2-abundant reticular (CAR) cells, which surround endothelial cells on sinusoids and arterioles or are located near the bone niche of HSCs.…”

Angiocrine ANGPTL2 executes HSC functions in endothelial niche

“…The most dramatic change observed in the BM niche during aging is excessive adipocyte expansion that presumably has a negative impact on HSC function. 9 An altered metabolic microenvironment in the stressed and aged BM might induce the defects observed in HSCs, setting the stage for myelodysplasia and hematopoietic failure during recovery from myeloablation. Because endothelial cells act as critical gatekeepers of tissue-specific metabolites, including free fatty acids, it is plausible that imbalanced metabolic fluxes and inflammatory stress within BMECs can result in aging-induced damage within the BM niche, thereby impairing HSC functions.…”