Abstract
Vascular regeneration depends on intact function of progenitors of vascular smooth muscle cells such as pericytes and their circulating counterparts, mesenchymal stromal cells (MSC). Deregulated MSC differentiation and maladaptive cell fate programs associated with age and metabolic diseases may exacerbate arteriosclerosis due to excessive transformation to osteoblast-like calcifying cells. Targeting mTOR, a central controller of differentiation and cell fates, could offer novel therapeutic perspectives. In a cell culture model for osteoblastic differentiation of pluripotent human MSC we found distinct roles for mTORC1 and mTORC2 in the regulation of differentiation towards calcifying osteoblasts via cell fate programs in a temporally-controlled sequence. Activation of mTORC1 with induction of cellular senescence and apoptosis were hallmarks of transition to a calcifying phenotype. Inhibition of mTORC1 with Rapamycin elicited reciprocal activation of mTORC2, enhanced autophagy and recruited anti-apoptotic signals, conferring protection from calcification. Pharmacologic and genetic negative interference with mTORC2 function or autophagy both abolished regenerative programs but induced cellular senescence, apoptosis, and calcification. Overexpression of the mTORC2 constituent rictor revealed that enhanced mTORC2 signaling without altered mTORC1 function was sufficient to inhibit calcification. Studies in mice reproduced the in vitro effects of mTOR modulation with Rapamycin on cell fates in vascular cells in vivo. Amplification of mTORC2 signaling promotes protective cell fates including autophagy to counteract osteoblast differentiation and calcification of MSC, representing a novel mTORC2 function. Regenerative approaches aimed at modulating mTOR network activation patterns hold promise for delaying age-related vascular diseases and treatment of accelerated arteriosclerosis in chronic metabolic conditions.
Highlights
Vascular regeneration depends on intact function of progenitors of vascular smooth muscle cells such as pericytes and their circulating counterparts, mesenchymal stromal cells (MSC)
Vascular regeneration depends on local vascular smooth muscle cell (VSMC) precursor cells, or pericytes[1,2,3], that are replenished by mesenchymal stromal cells (MSC)[4]
We found that degenerative cell fates associated with both, aging and metabolic diseases such as cellular senescence and apoptosis were activated during osteoblast differentiation of MSC while autophagy as a protective mechanism was reduced
Summary
Vascular regeneration depends on intact function of progenitors of vascular smooth muscle cells such as pericytes and their circulating counterparts, mesenchymal stromal cells (MSC). Chronic metabolic disease conditions such as diabetes mellitus or chronic kidney disease with uremia accelerate both detrimental clinical phenotypes[14] This involves mechanisms usually associated with age, such as premature cellular senescence and other cell fates[15] adversely affecting viability, adaptibility, and resistance to stress[10,11,16]. Preservation and restoration of physiologic MSC function for endogenous regeneration can be considered more effective than targeting terminally differentiated cells such as VSMC and osteoblast-like cells to counteract or even reverse accelerated vascular calcification in patients with pro-arteriosclerotic conditions. Direct involvement of specific branches of the mTOR signaling network in regulation of mammalian life-span[29], cellular senescence[25,30], and vascular smooth muscle and osteoblast differentiation[5,6,31,32] opens a perspective for therapeutic mTOR targeting in aging-related pathologies of the bone-vascular axis. Rapa has been shown to counteract degenerative and age-related pathologies in heart and brain[34,35], making it a prototypic candidate to stimulate endogenous regenerative processes
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