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Pharmacological Regulation of In Situ Tissue Stem Cells Differentiation for Soft Tissue Calcification Treatment
Jia-Jie Hu1,2, Zi Yin1,2, Wei-Liang Shen3
1Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Zhejiang, 310009, China.
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.
Insights
Hypoxia-inducible factor-2 alpha (HIF-2alpha) signaling drives soft tissue calcification by promoting osteochondrogenic differentiation of stem cells. Digoxin inhibits HIF-2alpha, offering a potential therapeutic strategy for treating calcification.
Area of Science:
- Biomedical Engineering
- Cell Biology
- Regenerative Medicine
Background:
- Soft tissue calcification, affecting heart valves and tendons, presents a significant clinical challenge with few treatment options.
- Tissue-specific stem and progenitor cells normally repair injuries but can differentiate into bone-forming cells in pathological environments.
Purpose of the Study:
- To investigate the role of HIF-2alpha signaling in stem/progenitor cells during soft tissue calcification.
- To explore the potential of pharmacological inhibition of HIF-2alpha as a therapeutic strategy.
Main Methods:
- Analysis of stem/progenitor cells from calcified human tendons and heart valves.
- Investigating the correlation between the inflammatory microenvironment and HIF-2alpha activation.
- Assessing the effect of HIF-2alpha on tendon stem/progenitor cell (TSPC) differentiation.
- Evaluating the impact of Scleraxis (Scx) transcription factor.
- Testing the efficacy of digoxin, a HIF-2alpha inhibitor, in vitro and in an Achilles' tendinopathy model.
Main Results:
- HIF-2alpha signaling is activated in stem/progenitor cells at calcified sites, driven by inflammation rather than hypoxia.
- Upregulated HIF-2alpha promotes osteochondrogenic differentiation and suppresses tenogenesis by inhibiting the Scx transcription factor.
- Digoxin effectively inhibited calcification and promoted tenogenesis in vitro and in vivo.
Conclusions:
- Aberrant HIF-2alpha signaling in tissue stem/progenitor cells is a key driver of soft tissue calcification.
- Pharmacological inhibition of HIF-2alpha represents a promising therapeutic avenue for treating soft tissue calcification.
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