Aging Reprograms the Hematopoietic-Vascular Niche to Impede Regeneration and Promote Fibrosis
| Autor: | Tinghong Ye, Hua Zhang, Zhongwei Cao, Chengjian Zhao, Xiaojuan Huang, Han-Min Liu, Lina Qiao, Yutian Chen, Yafeng Ren, Charles T. Esmon, Yongyuan Ma, Qiang Pu, Bi-Sen Ding |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Chemokine Aging Physiology Mice Transgenic 03 medical and health sciences Mice 0302 clinical medicine Fibrosis medicine Animals Platelet activation Stem Cell Niche Molecular Biology TIMP1 Endothelial protein C receptor biology business.industry Cell Biology medicine.disease Endothelial stem cell Haematopoiesis Crosstalk (biology) 030104 developmental biology biology.protein Cancer research business 030217 neurology & neurosurgery |
| Zdroj: | Cell metabolism. 33(2) |
| ISSN: | 1932-7420 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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