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Genetic lineage tracing reveals stellate cells as contributors to myofibroblasts in pancreas and islet fibrosis.

ABSTRACT: Pancreatic stellate cells (PSCs) are suggested to play an important role in the development of pancreas and islet fibrosis. However, the precise contributions and solid in vivo evidence of PSCs to the fibrogenesis remain to be elucidated. Here, we developed a novel fate-tracing strategy for PSCs by vitamin A administration in Lrat-cre; Rosa26-tdTomato transgenic mouse. The results showed that stellate cells give rise to 65.7% of myofibroblasts in cerulein-induced pancreatic exocrine fibrosis. In addition, stellate cells in islets increase and contribute partly to myofibroblasts pool in streptozocin-induced acute or chronic islet injury and fibrosis. Furthermore, we substantiated the functional contribution of PSCs to fibrogenesis of pancreatic exocrine and islet in PSCs ablated mice. We also found stellate cells' genetic ablation can improve pancreatic exocrine but not islet fibrosis. Together, our data indicates that stellate cells are vital/partial contributors to myofibroblasts in pancreatic exocrine/islet fibrosis.

SUBMITTER: Wang J

PROVIDER: S-EPMC10291507 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Genetic lineage tracing reveals stellate cells as contributors to myofibroblasts in pancreas and islet fibrosis.

Wang Jinbang J Li Tingting T Zhou Yunting Y Wang Xiaohang X Carvalho Vladmir V Ni Chengming C Li Wei W Wang Qianqian Q Chen Yang Y Shang Zhanjia Z Qiu Shanhu S Sun Zilin Z

iScience 20230526 6

Pancreatic stellate cells (PSCs) are suggested to play an important role in the development of pancreas and islet fibrosis. However, the precise contributions and solid <i>in vivo</i> evidence of PSCs to the fibrogenesis remain to be elucidated. Here, we developed a novel fate-tracing strategy for PSCs by vitamin A administration in Lrat-cre; Rosa26-tdTomato transgenic mouse. The results showed that stellate cells give rise to 65.7% of myofibroblasts in cerulein-induced pancreatic exocrine fibro ...[more]

PMID: 37378313

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Project description:AimsCardiac ischaemia does not elicit an efficient angiogenic response. Indeed, lack of surgical revascularization upon myocardial infarction results in cardiomyocyte death, scarring, and loss of contractile function. Clinical trials aimed at inducing therapeutic revascularization through the delivery of pro-angiogenic molecules after cardiac ischaemia have invariably failed, suggesting that endothelial cells in the heart cannot mount an efficient angiogenic response. To understand why the heart is a poorly angiogenic environment, here we compare the angiogenic response of the cardiac and skeletal muscle using a lineage tracing approach to genetically label sprouting endothelial cells.Methods and resultsWe observed that overexpression of the vascular endothelial growth factor in the skeletal muscle potently stimulated angiogenesis, resulting in the formation of a massive number of new capillaries and arterioles. In contrast, response to the same dose of the same factor in the heart was blunted and consisted in a modest increase in the number of new arterioles. By using Apelin-CreER mice to genetically label sprouting endothelial cells we observed that different pro-angiogenic stimuli activated Apelin expression in both muscle types to a similar extent, however, only in the skeletal muscle, these cells were able to sprout, form elongated vascular tubes activating Notch signalling, and became incorporated into arteries. In the heart, Apelin-positive cells transiently persisted and failed to give rise to new vessels. When we implanted cancer cells in different organs, the abortive angiogenic response in the heart resulted in a reduced expansion of the tumour mass.ConclusionOur genetic lineage tracing indicates that cardiac endothelial cells activate Apelin expression in response to pro-angiogenic stimuli but, different from those of the skeletal muscle, fail to proliferate and form mature and structured vessels. The poor angiogenic potential of the heart is associated with reduced tumour angiogenesis and growth of cancer cells.

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Genetic lineage tracing reveals stellate cells as contributors to myofibroblasts in pancreas and islet fibrosis.

Publications

Genetic lineage tracing reveals stellate cells as contributors to myofibroblasts in pancreas and islet fibrosis.

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