Decline in the function of stem cells with age, such as other cells of the body, results in an imbalance between loss and renewal. Increasing age of the donor thus diminishes the effectiveness of MSCs (mesenchymal stem cells) transplantation in age-related diseases. The clinical use of stem cell therapies needs autologous stem cell transplantation; it is essential therefore to study the repair ability and survivability of cells before transplantation. Bone marrow derived MSCs possess multi-lineage differentiation potential, but aging adversely affects their therapeutic efficacy. MSCs from young (2-3 months) and aged (23-24 months) GFP (green fluorescent protein)-expressing C57BL/6 mice were isolated and their regenerative potential was assessed in vitro. Real-time RT-PCR (reverse transcriptase-PCR) showed significantly higher expression of Sirt1 in MSCs isolated from young than older animals. Down-regulation of VEGF (vascular endothelial growth factor), SDF-1 (stromal-cell-derived factor 1), AKT (also known as protein kinase B) and up-regulation of p53, p21, Bax and p16 occurred in aged cells. Tube formation, wound healing and proliferative abilities of the young MSCs were better than the aged MSCs. The results suggest that age-related increased expression of apoptotic and senescent genes, with concomitant decrease in Sirt1 gene expression, inhibits to some extent stem cell functioning.
Mesenchymal stem cells (MSCs) are an attractive candidate for autologous cell therapy, but their ability to repair damaged myocardium is severely compromised with advanced age. Development of viable autologous cell therapy for treatment of heart failure in the elderly requires the need to address MSC ageing. In this study, MSCs from young (2 months) and aged (24 months) C57BL/6 mice were characterized for gene expression of IGF-1, FGF-2, VEGF, SIRT-1, AKT, p16INK4a, p21 and p53 along with measurements of population doubling (PD), superoxide dismutase (SOD) activity and apoptosis. Aged MSCs displayed senescent features compared with cells isolated from young animals and therefore were pre-conditioned with glucose depletion to enhance age affected function. Pre-conditioning of aged MSCs led to an increase in expression of IGF-1, AKT and SIRT-1 concomitant with enhanced viability, proliferation and delayed senescence. To determine the myocardial repair capability of pre-conditioned aged MSCs, myocardial infarction (MI) was induced in 24 months old C57BL/6 wild type mice and GFP expressing untreated and pre-conditioned aged MSCs were transplanted. Hearts transplanted with pre-conditioned aged MSCs showed increased expression of paracrine factors, such as IGF-1, FGF-2, VEGF and SDF-1α. This was associated with significantly improved cardiac performance as measured by dp/dtmax, dp/dtmin, LVEDP and LVDP, declined left ventricle (LV) fibrosis and apoptosis as measured by Masson's Trichrome and TUNEL assays, respectively, after 30 days of transplantation. In conclusion, pre-conditioning of aged MSCs with glucose depletion can enhance proliferation, delay senescence and restore the ability of aged cells to repair senescent infarcted myocardium.
Conventional approaches can repair minor skin injuries; however, severe burn injuries require innovative approaches for efficient and better wound repair. Recent studies indicate that stem cell-based regenerative therapies can restore severe damaged skin both structurally and functionally. The current study aims to evaluate the wound healing potential of skin substitute derived from human neonatal stem cells (hNSCs) using a severe burn injury rat model. Amniotic epithelial cells (AECs) and mesenchymal stem cells (MSCs) were isolated from placenta (a source of neonatal stem cells) by explant culture method. After characterization, AECs and umbilical cord-MSCs were differentiated into keratinocyte and fibroblasts, respectively. Morphological changes, and expression of corresponding keratinocyte and fibroblast specific markers were used to verify differentiation into respective lineage. A skin substitute was developed by mixing hNSCs-derived skin cells (hNSCs-SCs) in plasma for transplantation in a rat model of severe burn injury. Results indicated that placenta-derived AECs and MSCs were efficiently differentiated into skin cells, that is, keratinocytes and fibroblasts, respectively, as indicated by morphological changes, immunostaining, and polymerase chain reaction analysis. Further, transplantation of hNSCs-SCs seeded in plasma significantly improved basic skin architecture, re-epithelization rate, and wound healing concurrent with reduced apoptosis. In conclusion, neonatal stem cell-derived skin substitute efficiently improved severe burn wounds in a rat model of burn injury. Unique properties of placenta-derived stem cells make them superlative candidates for the development of "off-the-shelf" artificial skin substitutes for future use.
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