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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. We observed that HIF-2alpha (encoded by EPAS1 inclined form) signaling is markedly activated within stem\/progenitor cells recruited at calcified sites of diseased human tendons and heart valves. Proinflammatory microenvironment, rather than hypoxia, is correlated with HIF-2alpha activation and promoted osteochondrogenic differentiation of tendon stem\/progenitor cells (TSPCs). Abnormal upregulation of HIF-2alpha served as a key switch to direct TSPCs differentiation into osteochondral-lineage rather than teno-lineage. Notably, Scleraxis (Scx), an essential tendon specific transcription factor, was suppressed on constitutive activation of HIF-2alpha and mediated the effect of HIF-2alpha on TSPCs fate decision. 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.<\/jats:p>","DOI":"10.1002\/stem.2306","type":"journal-article","created":{"date-parts":[[2016,2,6]],"date-time":"2016-02-06T10:53:48Z","timestamp":1454756028000},"page":"1083-1096","source":"Crossref","is-referenced-by-count":40,"title":["Pharmacological Regulation of In Situ Tissue Stem Cells Differentiation for Soft Tissue Calcification Treatment"],"prefix":"10.1093","volume":"34","author":[{"given":"Jia-Jie","family":"Hu","sequence":"first","affiliation":[{"name":"Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Zhejiang, 310009, China"},{"name":"Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, 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