Abstract
Hematopoietic stem cells (HSC) could have several fates in the body; viz. self-renewal, differentiation, migration, quiescence, and apoptosis. These fate decisions play a crucial role in maintaining homeostasis and critically depend on the interaction of the HSCs with their micro-environmental constituents. However, the physiological cues promoting these interactions in vivo have not been identified to a great extent. Intense research using various in vitro and in vivo models is going on in various laboratories to understand the mechanisms involved in these interactions, as understanding of these mechanistic would greatly help in improving clinical transplantations. However, though these elegant studies have identified the molecular interactions involved in the process, harnessing these interactions to the recipients’ benefit would ultimately depend on manipulation of environmental cues initiating them in vivo: hence, these need to be identified at the earliest. HSCs reside in the bone marrow, which is a very complex tissue comprising of various types of stromal cells along with their secreted cytokines, extra-cellular matrix (ECM) molecules and extra-cellular vesicles (EVs). These components control the HSC fate decision through direct cell–cell interactions – mediated via various types of adhesion molecules –, cell-ECM interactions – mediated mostly via integrins –, or through soluble mediators like cytokines and EVs. This could be a very dynamic process involving multiple transient interactions acting concurrently or sequentially, and the adhesion molecules involved in various fate determining situations could be different. If the switch mechanisms governing these dynamic states in vivo are identified, they could be harnessed for the development of novel therapeutics. Here, in addition to reviewing the adhesion molecules involved in the regulation of HSCs, we also touch upon recent advances in our understanding of the physiological cues known to initiate specific adhesive interactions of HSCs with the marrow stromal cells or ECM molecules and EVs secreted by them.
Highlights
A hematopoietic stem cell (HSC) could have several fates in the body: it could remain quiescent; it could self-renew; it could commit to a particular lineage; it could migrate in response to a chemotactic cue; or it could even undergo apoptosis
Several studies have documented the adhesion mechanisms involved in the HSC fate decisions, the physiological cues that are translated into cellular language for the initiation of specific adhesive interactions of HSCs with stromal cells, or extra-cellular matrix (ECM) molecules and extra-cellular vesicles (EVs) secreted by them are not described to a great extent
We have shown that the cryopreservation of CD34+ human HSPCs in the presence of interleukin-3 (IL-3) and stem cell factor (SCF) increases the frequency of CD34 and L-selectin double positive HSCs in the revived cell population, along with an increased number of CFU-forming progenitors (Sasnoor et al, 2003), indicating the importance of L-selectin expression on human HSPCs
Summary
GRAPHICAL ABSTRACT | Hematopoietic stem cells (HSCs) reside in the bone marrow microenvironment comprising of various types of stromal cells and the ECM molecules secreted by them. This complex microenvironment forms the specialized HSC niche, which controls their maintenance, survival and fate decisions. The graphical abstract illustrates various molecules that have been shown to be expressed on the HSCs as well as stromal cells such as various integrins, N- cadherin, Notch, Ephrins, PSGL-1, CD162, CD44, etc. The illustration points out an as yet unexplored aspect of adhesive interactions between various stromal cells (e.g., between MSC-OB, MSC-EC etc., shown in dotted red lines)
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