title: Pharmacological Regulation of In Situ Tissue Stem Cells Differentiation for Soft Tissue Calcification Treatment.
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.
authors: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Zhejiang, 310009, China.|Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Zhejiang, 310009, China.
authors: Jia-Jie
authors: JJ
authors: Hu
authors: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Zhejiang, 310009, China.|Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Zhejiang, 310009, China.
authors: Zi
authors: Z
authors: Yin
authors: Department of Orthopedic Surgery, 2nd Affiliated Hospital , School of Medicine Zhejiang University, Zhejiang, 310009, China.
authors: Wei-Liang
authors: WL
authors: Shen
authors: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Zhejiang, 310009, China.|Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Zhejiang, 310009, China.
authors: Yu-Bin
authors: YB
authors: Xie
authors: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Zhejiang, 310009, China.|Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Zhejiang, 310009, China.
authors: Ting
authors: T
authors: Zhu
authors: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Zhejiang, 310009, China.|Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Zhejiang, 310009, China.
authors: Ping
authors: P
authors: Lu
authors: Department of Orthopedic Surgery, 1st Affiliated Hospital, School of Medicine Zhejiang University, Zhejiang, 310009, China.
authors: You-Zhi
authors: YZ
authors: Cai
authors: Department of Orthopedic Surgery, 2nd Affiliated Hospital , School of Medicine Zhejiang University, Zhejiang, 310009, China.
authors: Min-Jian
authors: MJ
authors: Kong
authors: Faculty of Dentistry, The University of Hong Kong, Hong Kong, China.
authors: Boon Chin
authors: BC
authors: Heng
authors: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Zhejiang, 310009, China.|Department of Biochemistry and Molecular Biology, Zhejiang University, Hangzhou, Zhejiang, 310000, China.
authors: Yi-Ting
authors: YT
authors: Zhou
authors: Department of Orthopedic Surgery, 2nd Affiliated Hospital , School of Medicine Zhejiang University, Zhejiang, 310009, China.
authors: Wei-Shan
authors: WS
authors: Chen
authors: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Zhejiang, 310009, China.|Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Zhejiang, 310009, China.
authors: Xiao
authors: X
authors: Chen
authors: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Zhejiang, 310009, China.|Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Zhejiang, 310009, China.|Department of Sports Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310000, China.|State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, 310003, Hangzhou, China.|China Orthopedic Regenerative Medicine Group (CORMed).
authors: Hong-Wei
authors: HW
authors: Ouyang
mesh_terms: D000125:Achilles Tendon / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D000368:Aged; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D002114:Calcinosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D060833:Cellular Microenvironment / Q000187:drug effects; D020219:Chondrogenesis / Q000235:genetics; D004077:Digoxin / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D051381:Rats; D012214:Rheumatic Heart Disease / Q000235:genetics / Q000473:pathology; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology; D064746:Therapy, Soft Tissue; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004077:Digoxin; D000099162:Endothelial PAS Domain-Containing Protein 1; C093504:SCX protein, human
keywords: Calcification; Digoxin; HIF-2 alpha; Heart valves; Stem cells; Tendons