Pharmacological Regulation of In Situ Tissue Stem Cells Differentiation for Soft Tissue Calcification Treatment

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Abstract
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. 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.
Funding Information
  • NSFC (81330041, 81125014, 81522029, 31570987, 31271041, 81401781, 81201396, 81271970, J1103603)
  • Zhejiang Provincial Natural Science Foundation of China (LR14H060001)
  • National High Technology Research and Development Program of China (2012AA020503)
  • International Science & Technology Cooperation Program of China (2015DFG32130)
  • Regenerative Medicine in Innovative Medical Subjects of Zhejiang Province. Medical and health science and technology plan of department of Health of Zhejiang Province (2013RCA010)
  • the Postdoctoral Foundation of China (2014M561775)
  • Key Scientific and Technological Innovation Team of Zhejiang Province (2013TD11)
  • Fundamental Research Funds for the Central Universities

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