Bone Marrow Micro‐Environment in Normal and Deranged Hematopoiesis: Opportunities for Regenerative Medicine and Therapies

Abstract

Various cell types cooperate to create a highly organized and dynamic micro-environmental niche in the bone marrow. Over the past several years, the field has increasingly recognized the critical roles of the interplay between bone marrow environment and hematopoietic cells in normal and deranged hematopoiesis. These advances rely on several new technologies that have allowed us to characterize the identity and roles of these niches in great detail. Here, we review the progress of the last several years, list some of the outstanding questions in the field and propose ways to target the diseased environment to better treat hematologic diseases. Understanding the extrinsic regulation by the niche will help boost hematopoiesis for regenerative medicine. Based on natural development of hematologic malignancies, we propose that combinatory targeting the niche and hematopoietic intrinsic mechanisms in early stages of hematopoietic malignancies may help eliminate minimal residual disease and have the highest efficacy.

Mechanoregulation in Hematopoiesis and Hematologic Disorders

“…Mutant hematopoietic cells are able to reprogram their surrounding niche to support disease progression [66]. The disrupted niche in turn secretes factors that favor the survival and expansion of these aberrant cells, resulting in a malignant "self-reinforcing niche" [29,[66][67][68][69]. In this way, the niche can be hijacked to disadvantage healthy HSCs and ultimately lead to bone marrow failure and other hematological disorders [66].…”

The chromatin remodeler Brg1 is required for formation and maintenance of hematopoietic stem cells

“…17 Here, we showed The generation of HSPCs is a major goal for regenerative medicine. 50 HSPCs often traffic to the bone marrow and implant into the microenvironmental niche. NO functions as an intercellular messenger molecule in bone marrow microenvironment, having an important role in HSPC growth and differentiation.…”

Bone Marrow Fat and Hematopoiesis

“…The bone marrow stroma is a mixture of mesenchymal stem/progenitor cells and their progenies, including adipocytes, osteolineage cells, pericytes, chondrocytes, and fibroblasts ( 29 ). BMAs, which are the most abundant type of cells in the bone marrow hematopoietic microenvironment, play a vital role in maintaining balance between proliferation and differentiation of hematopoietic stem/progenitor cells.…”

“…Among these cells, the vascular sinusoidal endothelial cells and perivascular BMSCs support the self-renewal of HSCs by secreting the cytokines chemokine stromal cell-derived factor CXCL12 and stem cell factor (SCF) that play important roles in hematopoiesis, spermatogenesis, and melanogenesis ( 31 ). On the other hand, mature hematopoietic cells and non-myelinating Schwann cells are involved in HSC quiescence and localization through various pathways, including the TGF-β and CXCL4 signaling pathways ( 29 ). Additionally, osteoblasts, BMSCs, and mature hematopoietic cells support multipotent and committed progenitors and play a crucial role in efficient lymphopoiesis, myelopoiesis, and erythropoiesis ( 29 ).…”

“…On the other hand, mature hematopoietic cells and non-myelinating Schwann cells are involved in HSC quiescence and localization through various pathways, including the TGF-β and CXCL4 signaling pathways ( 29 ). Additionally, osteoblasts, BMSCs, and mature hematopoietic cells support multipotent and committed progenitors and play a crucial role in efficient lymphopoiesis, myelopoiesis, and erythropoiesis ( 29 ). BMF gradually accumulates with age; this is accompanied by a decrease in HSCs ( 32 ).…”