The Hematopoietic Bone Marrow Niche Ecosystem

Abstract

The bone marrow (BM) microenvironment, also called the BM niche, is essential for the maintenance of fully functional blood cell formation (hematopoiesis) throughout life. Under physiologic conditions the niche protects hematopoietic stem cells (HSCs) from sustained or overstimulation. Acute or chronic stress deregulates hematopoiesis and some of these alterations occur indirectly via the niche. Effects on niche cells include skewing of its cellular composition, specific localization and molecular signals that differentially regulate the function of HSCs and their progeny. Importantly, while acute insults display only transient effects, repeated or chronic insults lead to sustained alterations of the niche, resulting in HSC deregulation. We here describe how changes in BM niche composition (ecosystem) and structure (remodeling) modulate activation of HSCs in situ. Current knowledge has revealed that upon chronic stimulation, BM remodeling is more extensive and otherwise quiescent HSCs may be lost due to diminished cellular maintenance processes, such as autophagy, ER stress response, and DNA repair. Features of aging in the BM ecology may be the consequence of intermittent stress responses, ultimately resulting in the degeneration of the supportive stem cell microenvironment. Both chronic stress and aging impair the functionality of HSCs and increase the overall susceptibility to development of diseases, including malignant transformation. To understand functional degeneration, an important prerequisite is to define distinguishing features of unperturbed niche homeostasis in different settings. A unique setting in this respect is xenotransplantation, in which human cells depend on niche factors produced by other species, some of which we will review. These insights should help to assess deviations from the steady state to actively protect and improve recovery of the niche ecosystem in situ to optimally sustain healthy hematopoiesis in experimental and clinical settings.

The Hematology of Tomorrow Is Here—Preclinical Models Are Not: Cell Therapy for Hematological Malignancies

“…Importantly, the greatest limitation of xenograft models is a mouse BM microenvironment to support human HSC engraftment and sustain human hematopoiesis. As of today, there is insufficient knowledge of the murine HSC niche cell types and molecular interactions involved [118]. For example, mouse CXCL12 binds and signals through human CXCR4, whereas other soluble factors such as osteopontin expressed by stromal cells including MSC and its receptors expressed on HSC, show only moderate protein identity between mouse and human, suggesting little contribution to human HSC maintenance in the mouse HSC niche [118][119][120].…”

“…As of today, there is insufficient knowledge of the murine HSC niche cell types and molecular interactions involved [118]. For example, mouse CXCL12 binds and signals through human CXCR4, whereas other soluble factors such as osteopontin expressed by stromal cells including MSC and its receptors expressed on HSC, show only moderate protein identity between mouse and human, suggesting little contribution to human HSC maintenance in the mouse HSC niche [118][119][120]. A potential strategy to overcome this milestone is to humanize the HSC niche.…”

Hematopoietic Progenitors and the Bone Marrow Niche Shape the Inflammatory Response and Contribute to Chronic Disease

“…What is currently unknown is whether cells of the BM niche contribute to the induction of trained immunity. Non-immune cells, such as endothelial cells and fibroblasts (both of which are major cellular constituents of the BM niche [234]), have been found to a adopt memory characteristics similar to that seen in innate cells [235,236]. Local production of developmental endothelial locus-1 (Del-1) [237] and G-CSF [39] by endothelial cells supports HSC expansion toward the myeloid lineage and endothelial cells express a range of PRRs that may enable interaction with various training stimuli [238].…”

Inflammaging, an Imbalanced Immune Response That Needs to Be Restored for Cancer Prevention and Treatment in the Elderly

“…Immunosenescence also occurs in the BM, which constitutes the primary site of hematopoiesis [11]. Thus, aging causes both a gradual replacement of the different cellular components of the BM by adipocytes and a skew towards the generation of myeloid cells [12].…”