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.

Keywords: HSC; cross-talk; hematological diseases; hematopoiesis; niche; premalignant; treatment.

Figure 1. Regulation Of Hematopoiesis By The Bone Marrow Microenvironment

a. Hematopoietic stem cells (HSC) are maintained and regulated by a variety of signals and cell-types in their perisinusoidal niche. Sinusoidial endothelial cells (Sinusoidal EC) and perivascular mesenchymal stromal cells (Perivascular MSC) support HSC self-renewal by release of SCF and CXCL-12. Mature hematopoietic cells and non-myelinating Schwann cells play roles in HSC quiescence and localization through various pathways, including TGF-β and CXCL4 signaling. A variety of physiologic and systemic cues modify HSC behavior through both direct and indirect signaling. b. The bone marrow microenvironment regulates downstream hematopoiesis. Osteoblasts, MSCs, and mature hematopoietic cells support multipotent and committed progenitors, and are crucial players in efficient lympho-, myelo-, and erythropoiesis.

Figure 2. Schematic of proposed mechanisms by which the bone marrow microenvironment influences malignant transformation

a. Premalignant hematopoietic cells are at a disadvantage during subclinical disease and constrained by highly evolved extrinsic signals from the native bone marrow microenvironment. These cells may be eliminated entirely or allowed to persist in a permissive state. b. A variety of local and systemic environmental factors, including stromal cell injury, can facilitate progression toward malignancy by disrupting homeostatic inhibitory signals and promoting secondary genetic events in premalignant hematopoietic cells. c. Malignant hematopoietic cells remodel the microenvironment. 1. Endosteal cells are hijacked by malignant plasma cells in multiple myeloma. Osteoclasts engage in abnormal bone resorption and osteoblasts provide a haven for malignant clone maintenance. 2. Deranged mesenchymal cells support malignant cell growth at the expense of normal hematopoiesis in MDS and AML. 3. Mesenchymal cells are directed toward myofibroblast differentiation in myelofibrosis. Extracellular matrix changes, including collagen and reticulin deposition, create a pro-inflammatory, fibrotic milieu that disrupts normal hematopoiesis.