Calcification of soft tissues, such as heart valves and tendons, is a common clinical problem with limited therapeutics. Tissue specific stem/progenitor cells proliferate to repopulate injured tissues. But some of them become divergent to the direction of ossification in the local pathological microenvironment, thereby representing a cellular target for pharmacological approach. The team led by Prof. Ouyang demonstrated an inflammation-activated signaling in stem/progenitor cells recruited at calcified sites, by which the HIF-2alpha (encoded by EPAS1) signaling represses Scleraxis (Scx) expression during tendon repair. Abnormal upregulation of HIF-2alpha served as a key switch to direct tendon stem/progenitor cells (TSPCs) differentiation into osteochondral-lineage rather than teno-lineage. Moreover, pharmacological inhibition of HIF-2alpha with digoxin, which is a widely utilized drug, can efficiently inhibit calcification and enhance tenogenesis in vitro and in the Achilles's tendinopathy model. Taken together, these findings reveal the significant role of the tissue stem/progenitor cells fate decision and suggest that pharmacological regulation of HIF-2alpha function is a promising approach for soft tissue calcification treatment.

 

Dr. HU JJ and YIN Z are co-first authors of this paper. This study was supported by grants from National Natural Science Foundation of China and The National Science Fund for Distinguished Young Scholars of China.

 

Schematic representation of the mechanisms through which digoxin may be affecting soft tissue stem/progenitor cells fate decision.