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

• Published in: Stem cells (Dayton, Ohio) Vol. 34; no. 4; pp. 1083 - 1096
• Main Authors: Hu, Jia‐Jie, Yin, Zi, Shen, Wei‐Liang, Xie, Yu‐Bin, Zhu, Ting, Lu, Ping, Cai, You‐Zhi, Kong, Min‐Jian, Heng, Boon Chin, Zhou, Yi‐Ting, Chen, Wei‐Shan, Chen, Xiao, Ouyang, Hong‐Wei
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.04.2016
• Subjects: Achilles Tendon - drug effects; Achilles Tendon - growth & development; Achilles Tendon - pathology; Aged; Animals; Basic Helix-Loop-Helix Transcription Factors - antagonists & inhibitors; Basic Helix-Loop-Helix Transcription Factors - biosynthesis; Basic Helix-Loop-Helix Transcription Factors - genetics; Calcification; Calcinosis - drug therapy; Calcinosis - genetics; Calcinosis - pathology; Cell Differentiation - genetics; Cell Proliferation - drug effects; Cells, Cultured; Cellular Microenvironment - drug effects; Chondrogenesis - genetics; Digoxin; Digoxin - administration & dosage; Genes; Heart valves; HIF‐2 alpha; Humans; Male; Middle Aged; Rats; Rheumatic Heart Disease - genetics; Rheumatic Heart Disease - pathology; Stem cells; Stem Cells - drug effects; Stem Cells - pathology; Tendons; Therapy, Soft Tissue; Calcification; HIF-2 alpha; Digoxin; Heart valves; Stem cells; Tendons
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.2306

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. Stem Cells 2016;34:1083–1096