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Review
. 2021 Jul 22:9:705410.
doi: 10.3389/fcell.2021.705410. eCollection 2021.

The Hematopoietic Bone Marrow Niche Ecosystem

Julia Fröbel  1 , Theresa Landspersky  2 , Gülce Percin  1 , Christina Schreck  2 , Susann Rahmig  1 , Alessandro Ori  3 , Daniel Nowak  4 , Marieke Essers  5   6 , Claudia Waskow  1   7   8 , Robert A J Oostendorp  2
Affiliations
Review

The Hematopoietic Bone Marrow Niche Ecosystem

Julia Fröbel et al. Front Cell Dev Biol. .

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.

Keywords: aging; bone marrow; hematopoiesis; leukemia; microenvironment; niche; transplantation; xenograft.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Hypothesis of how repeated stress may progressively change the fitness of BM niche cells. After each cycle of stress, some damage remains. This low frequency changes the transcriptional, proteomic, and ecological BM niche cellular composition landscapes over time. Eventually, aging-like changes in the BM niche result in loss of functional HSCs, systemic inflammation, and development of chronic alterations with loss of niche support for healthy hematopoiesis in the BM. Instead, the altered niche supports the development of chronic malignancies.
FIGURE 2
FIGURE 2
Schematic representation of molecular communication partners between HSCs and their niche. The ligands produced by each niche cell are indicated. Color of receptors correlates to the number of ligand-secreting cell types (dark – many producers, light – few producers). Adi, adipocyte; EC, endothelial cell; Mk, megakaryocyte; Mp, macrophage; MSC, mesenchymal stromal cell; Ob, osteoblast; SC, Schwann cell; SNS, sympathetic nervous system.
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