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

TitlePharmacological Regulation of In Situ Tissue Stem Cells Differentiation for Soft Tissue Calcification Treatment.
Authors
Issue Date2016
Citation
Stem Cells, 2016, v. 34, p. 1083-96 How to Cite?
AbstractCalcification 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.
Persistent Identifierhttp://hdl.handle.net/10722/234476

 

DC FieldValueLanguage
dc.contributor.authorHu, JJ-
dc.contributor.authorYin, Z-
dc.contributor.authorShen, WL-
dc.contributor.authorXie, YB-
dc.contributor.authorZhu, T-
dc.contributor.authorLu, P-
dc.contributor.authorCai, YZ-
dc.contributor.authorKong, MJ-
dc.contributor.authorHeng, BCA-
dc.contributor.authorZhou, YT-
dc.contributor.authorChen, WS-
dc.contributor.authorChen, X-
dc.contributor.authorOuyang, HW-
dc.date.accessioned2016-10-14T13:47:08Z-
dc.date.available2016-10-14T13:47:08Z-
dc.date.issued2016-
dc.identifier.citationStem Cells, 2016, v. 34, p. 1083-96-
dc.identifier.urihttp://hdl.handle.net/10722/234476-
dc.description.abstractCalcification 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.-
dc.languageeng-
dc.relation.ispartofStem Cells-
dc.titlePharmacological Regulation of In Situ Tissue Stem Cells Differentiation for Soft Tissue Calcification Treatment.-
dc.typeArticle-
dc.identifier.emailHeng, BCA: alexish@hku.hk-
dc.identifier.doi10.1002/stem.2306-
dc.identifier.hkuros270332-
dc.identifier.volume34-
dc.identifier.spage1083-
dc.identifier.epage96-

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