1,25-Dihydroxyvitamin D3 Treatment Delays Cellular Aging in Human Mesenchymal Stem Cells while Maintaining Their Multipotent Capacity

Abstract

1,25-dihydroxyvitamin D3 (1,25D3) was reported to induce premature organismal aging in fibroblast growth factor-23 (Fgf23) and klotho deficient mice, which is of main interest as 1,25D3 supplementation of its precursor cholecalciferol is used in basic osteoporosis treatment. We wanted to know if 1,25D3 is able to modulate aging processes on a cellular level in human mesenchymal stem cells (hMSC). Effects of 100 nM 1,25D3 on hMSC were analyzed by cell proliferation and apoptosis assay, β-galactosidase staining, VDR and surface marker immunocytochemistry, RT-PCR of 1,25D3-responsive, quiescence- and replicative senescence-associated genes. 1,25D3 treatment significantly inhibited hMSC proliferation and apoptosis after 72 h and delayed the development of replicative senescence in long-term cultures according to β-galactosidase staining and P16 expression. Cell morphology changed from a fibroblast like appearance to broad and rounded shapes. Long term treatment did not induce lineage commitment in terms of osteogenic pathways but maintained their clonogenic capacity, their surface marker characteristics (expression of CD73, CD90, CD105) and their multipotency to develop towards the chondrogenic, adipogenic and osteogenic pathways. In conclusion, 1,25D3 delays replicative senescence in primary hMSC while the pro-aging effects seen in mouse models might mainly be due to elevated systemic phosphate levels, which propagate organismal aging.

Calcitriol modulates the effects of the supernatants of bone-marrow–derived mesenchymal stem cells on neutrophil functions

“…After activation, MSCs mediate immunosuppression through the secretion of soluble mediators (such as nitric oxide, prostaglandin E2, indoleamine 2,3-dioxygenase, and IL-6) and up-regulation of modulatory molecules (including galectins, PDL1, TGF-β, and HLA-G) (Meisel et al, 2004;Maby-El Hajjami et al, 2009;Ghannam et al, 2010). Recent evidence has demonstrated that calcitriol inhibits MSC-proliferationinduced cell cycle arrest and promotes accumulation of MSCs in the G0/G1 phase without inducing apoptosis (Artaza et al, 2010;Klotz et al, 2012). These effects were associated with a decrease in the GTPase Rho and the atypical Rho family GTPase Rhou/Wrch-1 expression without inducing Wnt-1 expression.…”

“…Recent documents have shown that calcitriol has an important role in regulating the growth of MSCs (Artaza et al, 2010;Klotz et al, 2012). The present study was carried out to investigate the effects of calcitriol on the interaction between bone-marrow-derived MSCs and neutrophils in rats.…”

The Role of Vitamin D Deficiency and Vitamin D Receptor Genotypes on the Degree of Collateralization in Patients with Suspected Coronary Artery Disease

“…The precise mechanism of how the ligand/VDR complex may help protect individuals against cardiovascular diseases is not clear. It has been documented that vitamin D has functional roles in cellular proliferation, including different stages of the cell cycle, differentiation, and apoptosis [17, 18] that could have impact on normal angiogenesis and endothelial cell differentiation [19]. VDR is expressed in almost all tissues and in a wide variety of cell types, including cardiomyocytes, vascular smooth muscle cells, and endothelial cells [20, 21].…”

Strategies to Enhance the Effectiveness of Adult Stem Cell Therapy for Ischemic Heart Diseases Affecting the Elderly Patients

“…One technique for accomplishing this is the treatment of cells in vitro with 1,25-dihydroxyvitamin D3 [39]. Klotz et al showed that treatment of human mesenchymal stem cells with 1,25-dihydroxyvitamin D3 (1,25D3) delays signs of senescence while simultaneously helping the stem cells retain their multipotent capacities (Fig.…”

“…Additionally, the treated cells showed down-regulated expression of the aging-related gene p16 INK4a , and significantly less cell death after 72 h when compared to the control groups. However, the 1,25D3 treatment simply delayed senescence while allowing the cells to retain their multi-potent qualities; it did not influence the cells to differentiate into any specific lineage, so if this treatment is to be used, it must be used in conjunction with a differentiating agent [39]. To retain multi-potency, it is essential to conserve a population of quiescent cells so that in case of future injury, these cells can readily contribute to the healing process.…”