Inhibition of SRC-mediated integrin signaling in bone marrow niche enhances hematopoietic stem cell function

Interaction with microenvironmental factors is crucial for the regulation of hematopoietic stem cell (HSC) function. Stroma derived factor (SDF)-1 alpha supports HSCs in the quiescent state and is central to the homing of transplanted HSCs. Here, we show that integrin signaling regulates Sdf-1 alpha expression transcription-ally. Systemic deletion of Periostin, an Integrin-alpha v ligand, showed increased expression of Sdf-1 alpha in bone marrow (BM) niche. Pharmacological inhibition or CRISPR-Cas9-mediated deletion of SRC, resulted in a similar increase in the chemokine expression in vitro. Importantly, systemic SRC-inhibition led to increase in SDF-1 alpha levels in BM plasma. This resulted in a robust increase (14.05 +/- 1.22% to 29.11 +/- 0.69%) in the homing efficiency of transplanted HSCs. In addition, we observed enhancement in the recovery of blood cell counts following radiation injury, indicating an enhanced hematopoietic function. These results establish a role of SRC-mediated integrin signaling in the transcriptional regulation of Sdf-1 alpha. This mechanism could be harnessed further to improve the hematopoietic function.