Bone marrow-derived mesenchymal stem cells (MSCs) have
therapeutic effects in experimental models of
lung injury.
Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcriptional regulator that influences cellular metabolism, energetics, and survival under hypoxic conditions. The current study investigated the effects of stabilizing HIF-1α on the therapeutic capacity of MSCs in an experimental mouse model of
bacterial pneumonia. HIF-1α stabilization was achieved by the small molecule prolyl-hydroxlase inhibitor,
AKB-4924 (Aerpio
Therapeutics, Inc.), which blocks the pathway for HIF-1α degradation in the proteosome. In vitro, pre-treatment with
AKB-4924 increased HIF-1α levels in MSCs, reduced the kinetics of their cell death when exposed to cytotoxic stimuli, and increased their antibacterial capacity. In vivo,
AKB-4924 enhanced MSC therapeutic capacity in experimental
pneumonia as quantified by a sustainable survival benefit, greater bacterial clearance from the lung, decreased
lung injury, and reduced inflammatory indices. These results suggest that HIF-1α stabilization in MSCs, achieved ex vivo, may represent a promising approach to augment the therapeutic benefit of these cells in severe
pneumonia complicated by
acute lung injury.