Aging Reprograms the Hematopoietic-Vascular Niche to Impede Regeneration and Promote Fibrosis

Regenerative capacity is frequently impaired in aged organs. Stress to aged organs often causes scar formation (fibrosis) at the expense of regeneration. It remains to be defined how hematopoietic and vascular cells contribute to aging-induced regeneration to fibrotic transition. Here, we find that...

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Bibliographic Details
Published in:Cell metabolism 2021-02, Vol.33 (2), p.395-410.e4
Main Authors: Chen, Yutian, Pu, Qiang, Ma, Yongyuan, Zhang, Hua, Ye, Tinghong, Zhao, Chengjian, Huang, Xiaojuan, Ren, Yafeng, Qiao, Lina, Liu, Han-Min, Esmon, Charles T., Ding, Bi-Sen, Cao, Zhongwei
Format: Article
Language:English
Subjects:
aging
endothelial cell
endothelial protein C receptor
hypoxia-inducible factor 2 alpha
interleukin-1alpha
liver fibrosis
lung fibrosis
macrophage
neuropilin1
platelet
vascular niche
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Summary:Regenerative capacity is frequently impaired in aged organs. Stress to aged organs often causes scar formation (fibrosis) at the expense of regeneration. It remains to be defined how hematopoietic and vascular cells contribute to aging-induced regeneration to fibrotic transition. Here, we find that aging aberrantly reprograms the crosstalk between hematopoietic and vascular cells to impede the regenerative capacity and enhance fibrosis. In aged lung, liver, and kidney, induction of Neuropilin-1/hypoxia-inducible-factor 2α (HIF2α) suppresses anti-thrombotic and anti-inflammatory endothelial protein C receptor (EPCR) pathway, leading to formation of pro-fibrotic platelet-macrophage rosette. Activated platelets via supplying interleukin 1α synergize with endothelial-produced angiocrine chemokine to recruit fibrogenic TIMP1high macrophages. In mouse models, genetic targeting of endothelial Neuropilin-1-HIF2α, platelet interleukin 1α, or macrophage TIMP1 normalized the pro-fibrotic hematopoietic-vascular niche and restored the regenerative capacity of old organs. Targeting of aberrant endothelial node molecules might help propel “regeneration without scarring” in the repair of multiple organs. [Display omitted] •Aging reprograms the hematopoietic-vascular niche to impede organ regeneration•Reprogrammed hematopoietic-vascular niche stimulates fibrosis in old organs•Targeting node molecules normalizes aging-reprogramed hematopoietic-vascular niche•Normalizing the hematopoietic-vascular niche promotes regeneration without scar Chen et al. show that aging reprograms the crosstalk between vascular and hematopoietic cells to impede regeneration in multiple old organs. Aberrant induction of Neuropilin1 and HIF2α in endothelial cells suppresses endothelial protein C receptor (EPCR) after injury. This activates platelets and macrophages, forming a fibrogenic hematopoietic niche suppressing regeneration.
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2020.11.019