Integrins are known to promote the quiescence of hematopoietic stem cells (HSCs), but the precise mechanism has been unclear. In this issue, Ruppert et al. use mice deficient in Kindlin-3 (K3), an intracellular protein that regulates bidirectional integrin signaling, to show that integrin function differentially regulates quiescent and activated HSCs in the bone marrow (BM).
HSC quiescence is a defining behavior associated with preservation of self-renewal. Integrins have been shown to promote HSC homing to and retention in the BM and also to regulate HSC function. For example, deletion of α4 integrin, an adhesion molecule critical for HSC migration and homing, does not alter BM HSC numbers in the steady state but reduces HSC activity in the context of competitive reconstitution. It has been difficult, however, to tease apart the homing deficit from an intrinsic function of the integrin in HSC maintenance.
Ruppert et al. used a series of elegant experimental approaches to show convincingly that integrin function was dispensable for quiescent, long-term repopulating cells but was essential for activated HSCs and progenitors. One of the most convincing pieces of evidence was obtained from mixed chimeric mice harboring both K3+/+ and K3−/− HSCs, in which deletion of K3 was induced after stable engraftment in the BM, allowing the authors to bypass the homing step. This approach revealed that K3+/+ HSC numbers were sustained, whereas K3−/− progenitors were progressively depleted in the steady-state BM. The increased cycling of K3−/− versus K3+/+ progenitors was confirmed by BrdU labeling and 5-fluorouracil, which selectively labels and kills, respectively, cycling HSCs/progenitors. Proliferative HSCs and progenitors were not retained in the BM and were mobilized in blood and spleen, a finding consistent with the notion that integrins contribute to retention in BM. This study strongly supports the idea the K3 (and integrin activation) is dispensable for HSC maintenance under homeostasis but essential for progenitors when the hematopoietic system is under stress.
The differential requirement of quiescent and activated HSCs for integrin-mediated adhesion argues for hitherto unknown regional specifications of niche components and/or extracellular matrices maintaining active and quiescent HSCs. Although at first glance one can envision that integrins enable HSC migration toward a niche that promotes active cell divisions, the study by Ruppert et al. shows that integrin signaling exerts critical roles for retention in the BM, whereas it appears completely dispensable for the migration out of the marrow. Indeed, HSCs/progenitors deficient in activated integrins are readily mobilized, suggesting that integrin signaling, rather than its physical migratory function, may drive the phenotype in the active niche. The question then arises how dormant HSCs are anchored in their quiescent microenvironment. This question remains puzzling because signaling downstream of CXCR4/CXCL12, the sole niche factor–receptor pair thus far shown to promote HSC quiescence, leads to integrin activation. The most intuitive answer, as suggested by the authors, may lie in the overlapping array of adhesion receptors that could compensate for any individual loss. Additionally, other physical forces (e.g., neighboring cells and matrix) may contribute to maintain niche integrity without the specific need of brute adhesion strength.