Mechanoregulation in Hematopoiesis and Hematologic Disorders

Abstract

Purpose of Review Hematopoietic stem cells (HSCs) are reliant on intrinsic and extrinsic factors for tight control of self-renewal, quiescence, differentiation, and homing. Given the intimate relationship between HSCs and their niche, increasing numbers of studies are examining how biophysical cues in the hematopoietic microenvironment impact HSC functions. Recent Findings Numerous mechanosensors are present on hematopoietic cells, including integrins, mechanosensitive ion channels, and primary cilia. Integrin-ligand adhesion, in particular, has been found to be critical for homing and anchoring of HSCs and progenitors in the bone marrow. Integrin-mediated interactions with ligands present on extracellular matrix and endothelial cells are key to establishing long-term engraftment and quiescence of HSCs. Importantly, disruption in the architecture and cellular composition of the bone marrow associated with conditioning regimens and primary myelofibrosis exposes HSCs to a profoundly distinct mechanical environment, with potential implications for progression of hematologic dysfunction and pathologies. Summary Study of the mechanobiological signals that govern hematopoiesis represents an important future step toward understanding HSC biology in homeostasis, aging, and cancer.

Differentiation of human induced pluripotent stem cells into erythroid cells

“…Although HSCs can be used for the treatment of hematological disorders [66,67], the bone marrow biopsy is an invasive procedure with chronic graftversus-host diseases (GVHD), morbidity, and mortality in patients who received allogeneic HSC therapy [68,69]. Autologous HSCs are an alternative option with a lower mortality rate, though in some cases, genetic correction is necessary before autologous HSCs transplantation [70][71][72].…”

Biomechanical Regulation of Hematopoietic Stem Cells in the Developing Embryo

“…2b). YAP is a co-transcription factor that translocates to the nucleus in response to biomechanical force to contribute to cell fate decisions and has been shown to be regulated by Hippo and Wnt signaling, pathways important for HSC development [3,43,103,104]. Human induced pluripotent stem cell (iPSC) derived hemogenic endothelial cells were exposed to WSS or circumferential strain conditions and, while both treatment conditions increased Runx1 expression, cells exposed to WSS exhibited a more significant increase in Runx1 than cells exposed to circumferential strain [103].…”

“…Hematopoiesis is the process of generation and maintenance of the various cells of the blood and immune systems [1]. Hematopoiesis originates with hematopoietic stem cells (HSCs), which differentiate into a diverse array of cell lineages and are able to self-renew, allowing them to continually replenish short-term progenitors and mature blood cells [2,3]. This process is tightly regulated to prevent aberrant hematopoiesis, which can lead to hematologic disorders and malignancies [4].…”

“…The dynamic nature of adherens junctions may provide an explanation for some of the molecular changes that are observed during EHT. Together with PECAM-1 and VEGF-R2, VE-cadherin has been shown to activate MAPK, Akt, and PI3K signaling pathways, which have all been implicated in hematopoiesis [3,[62][63][64]. It is important to note that force has also been shown to activate mechanosensitive ion channels [3,65].…”

“…Together with PECAM-1 and VEGF-R2, VE-cadherin has been shown to activate MAPK, Akt, and PI3K signaling pathways, which have all been implicated in hematopoiesis [3,[62][63][64]. It is important to note that force has also been shown to activate mechanosensitive ion channels [3,65]. In a zebrafish model analyzing the impact of blood flow on endothelial cell extrusion, the mechanosensitive cationic channel polycystic kidney disease 2 (pkd2) was found to be responsible for modulating endothelial cell extrusion independent of primary cilia [65].…”