The science behind the hypoxic niche of hematopoietic stem and progenitors

Abstract

In blood, oxygen is transported principally by hemoglobin tetrameric molecules in erythocytes, which allow for the delivery to tissue cells. When anemia occurs, such as perisurgically or after trauma, blood transfusion is administered to replace the deficit in oxygen-carrying capacity. During embryogenesis and later in adult life, tissue oxygen levels control multiple key cellular functions. Low tissue oxygen levels in particular are physiologically relevant to stem cells by controlling their metabolism and cell fate. In adult life, hematopoietic stem cells reside in specified BM microenvironments/niches, where their quiescence and differentiation are presumably also influenced by cell-intrinsic and cell-extrinsic (niche) factors. Novel imaging technologies have allowed determination of the spatial localization of hematopoietic stem/progenitor cells (HSPCs), as well as the topography of oxygen distribution in BM cavities. Together, these recent advances have contributed to the emergence of a novel model that challenges the previous concept of a hypoxic hematopoietic stem cell niche characterized by poorly perfused endosteal zones with the deepest hypoxia. HSPCs display a hypoxic phenotype despite residing in close association with arterial or sinusoidal vascular networks. The entire BM cavity is hypoxic and unexpectedly exhibits an opposite oxygen gradient to the one initially proposed because arteriole-rich endosteal zones are relatively less hypoxic than deeper regions of the BM perfused by dense sinusoidal networks. Therefore, further studies are warranted to elucidate to what extent differences in oxygen tensions in these diverse microenvironments influence HSPC homeostasis. Learning Objective• To understand the fundamental basic research carried out to investigate the relevance of hypoxic conditions in bone marrow microenvironments that support hematopoietic stem cell maintenance Oxygen in tissues and stem cell biologyDuring evolution, fluctuations in atmospheric oxygen concentration have defined eukaryotic life forms on earth, exemplified by the adoption of efficient oxidative phosphorylation (ie, aerobic metabolism) to support more complex and multicellular organisms. 1

Urothelial cell expansion and differentiation are improved by exposure to hypoxia

“…Culture conditions under hypoxia switched the metabolism of the cells from aerobic to anaerobic and reduced the mitochondrial respiration, which correlates with increased glycolysis rates and reduced ROS production (Saito et al ., ). Therefore, an increase in the acidification of the cell culture medium that we observed under hypoxia conditions (data not shown) could be related to this metabolic switch without affecting cell proliferation (data not shown), which correlates with previous studies (Nombela‐Arrieta and Silberstein, ; Turner et al ., ; Wang et al ., ). Other molecules could also play a role in regulating cell stemness in response to hypoxia.…”

Quantification and three-dimensional microanatomical organization of the bone marrow

“…Many of the niches are constructed around diverse microvessel types, which distinctly regulate access to nutrients, oxygen, and metabolites derived from circulating blood. [64][65][66] Nevertheless, for the most part, available data on BM subcompartments remain fragmentary, and a broader picture integrating comprehensive spatial patterns and number of niches in an organ-wide context is lacking. In fact, only a limited number of studies have analyzed cell subset localization at a global scale and thus explored the hypothesis that hematopoietic cells distribute in a nonarbitrary fashion in accordance to a defined zonation of the BM landscape.…”

Hematopoietic stem cells under pressure

“…The h-Niche is irrigated with a heterogeneous network of arterioles, which carry oxygenated blood and are most abundant near the endosteum, and sinusoids, which carry less oxygenated blood and are abundant in the central BM (20, 47–49). This creates an oxygen gradient in the BM, from ≈4% O 2 near the endosteum to ≈2% in the central marrow (50, 51). However, the distribution of HSCs throughout the BM suggests that HSC maintain a hypoxic profile regardless of their location and external O 2 tension (24, 47, 48, 50–52).…”

“…This creates an oxygen gradient in the BM, from ≈4% O 2 near the endosteum to ≈2% in the central marrow (50, 51). However, the distribution of HSCs throughout the BM suggests that HSC maintain a hypoxic profile regardless of their location and external O 2 tension (24, 47, 48, 50–52). Although it is formally possible that super-low O 2 levels might exist in tight regions proximal to HSCs (50).…”