Hypoxia-Inducible Factor-1α Is Essential for Hypoxia-Induced Mesenchymal Stem Cell Mobilization into the Peripheral Blood

Abstract

Mobilization of mesenchymal stem cells (MSCs) is a promising strategy for tissue repair and regenerative medicine. The establishment of an appropriate animal model and clarification of the underlying mechanisms are beneficial to develop the mobilization regimens for therapeutic use. In this study, we therefore established a rat MSC mobilization model and investigated the related mechanisms, using continuous hypoxia as the mobilizing stimulus. We found that MSCs could be mobilized into peripheral blood of rats exposed to short-term hypoxia (2 days) and the mobilization efficiency increased in a time-dependent manner (2-14 days). Hypoxia-inducible factor-1α (HIF-1α) was upregulated during hypoxic exposure and was expressed continuously in bone marrow. Inhibition of HIF-1α expression by YC-1 remarkably reduced the number of mobilized MSCs, suggesting that HIF-1α is essential for hypoxia-induced MSC mobilization. Further, we investigated the potential role of HIF-1α target genes, vascular endothelial growth factor (VEGF), and stromal cell-derived factor-1α (SDF-1α). VEGF expression was elevated from day 2 to day 7 of hypoxia, stimulating an increase in bone marrow sinusoidal vessels and possibly facilitating the egress of MSCs. SDF-1α protein levels were increased in the peripheral blood of rats during MSC mobilization and promoted the migration of MSCs under hypoxic conditions in vitro. These results suggest that HIF-1α plays a pivotal role in hypoxia-induced MSC mobilization, possibly acting via its downstream genes VEGF and SDF-1α. These data provide a novel insight into the mechanisms responsible for MSC mobilization and may help in the development of clinically useful therapeutic agents.

Lysophosphatidic Acid Protects Human Mesenchymal Stromal Cells from Differentiation-Dependent Vulnerability to Apoptosis

“…43 Although MSC do not express VEGF receptors, 44 they produce increased amounts of VEGF in response to ischemia. [45][46][47] Indeed, MSC conditioned in GM secreted significantly higher levels of VEGF in SD/H, which was further augmented by the addition of 25 mM LPA (Fig. 5A).…”

Resident PW1 + Progenitor Cells Participate in Vascular Remodeling During Pulmonary Arterial Hypertension

“…41 Another common mechanism between the 2 models could involve HIF-1α as it is well established that inflammation causes a hypoxia-independent HIF-1α activation in response to the proinflammatory interleukin-1β. 42 HIF-1α regulates stem cells mobilization 43 and could therefore be involved in the recruitment of PW1 + progenitor cells. Finally, we demonstrate the presence of the PW1 + cells in the parenchyma and perivascular zones in the control human lung.…”

Enhanced osteogenic potential of mesenchymal stem cells from cortical bone: a comparative analysis

“…Hypoxia-inducible factor (HIF) is the major regulator of cellular hypoxic responses and is known to be upregulated in MSCs [68]. Furthermore, it has been reported that HIF is essential for peripheral blood MSC mobilization seen in hypoxia [69]. A deeper understanding of the activation of hypoxia response pathways in the CBF-MSCs may elucidate the mechanisms leading to the enhanced biosynthetic activity and is the subject of our ongoing investigations in this cell population.…”