Mitochondrial Function and Energy Metabolism in Umbilical Cord Blood- and Bone Marrow-Derived Mesenchymal Stem Cells

Abstract

Human mesenchymal stem cells (hMSCs) are an attractive choice for a variety of cellular therapies. hMSCs can be isolated from many different tissues and possess unique mitochondrial properties that can be used to determine their differentiation potential. Mitochondrial properties may possibly be used as a quality measure of hMSC-based products. Accordingly, the present work focuses on the mitochondrial function of hMSCs from umbilical cord blood (UCBMSC) cells and bone marrow cells from donors younger than 18 years of age (BMMSC <18) and those more than 50 years of age (BMMSC >50). Changes of ultrastructure and energy metabolism during osteogenic differentiation in all hMSC types were studied in detail. Results show that despite similar surface antigen characteristics, the UCBMSCs had smaller cell surface area and possessed more abundant rough endoplasmic reticulum than BMMSC >50. BMMSC <18 were morphologically more UCBMSC-like. UCBMSC showed dramatically higher mitochondrial-to-cytoplasm area ratio and elevated superoxide and manganese superoxide dismutase (MnSOD) levels as compared with BMMSC >50 and BMMSC <18. All hMSCs types showed changes indicative of mitochondrial activation after 2 weeks of osteogenic differentiation, and the increase in mitochondrial-to-cytoplasm area ratio appears to be one of the first steps in the differentiation process. However, BMMSC >50 showed a lower level of mitochondrial maturation and differentiation capacity. UCBMSCs and BMMSCs also showed a different pattern of exocytosed proteins and glycoproteoglycansins. These results indicate that hMSCs with similar cell surface antigen expression have different mitochondrial and functional properties, suggesting different maturation levels and other significant biological variations of the hMSCs. Therefore, it appears that mitochondrial analysis presents useful characterization criteria for hMSCs intended for clinical use.

Extracellular matrix modulates the biological effects of melatonin in mesenchymal stem cells

“…In the presence of 2-ME, a SOD2 inhibitor, BM-MSCs showed a marked increase in ROS production and suppression of osteoblast-specific marker genes. This was consistent with the finding that stem cells from aged donors, with lower levels of SOD2, exhibited a loss of differentiation capacity (Pietila et al 2012).…”

Connecting Mitochondria, Metabolism, and Stem Cell Fate

“…The development of the mitochondrial network precedes the loss of the pluripotency markers, OCT4 and Nanog, in differentiating hESCs [6]. Mitochondrial biogenesis and metabolic shift toward OXPHOS are also early events in osteogenic [37,39], adipogenic [34], and hepatogenic [40] differentiation of hMSCs. In mHSCs, the upregulation of mitochondrial biogenesis was demonstrated to parallel the loss of pluripotency [41].…”

“…Inhibiting mitochondrial biogenesis by the repression of PGC-1a [36] or mitochondrial transcription factor A (TFAM) [33] impairs adipogenic differentiation, as does rotenoneinduced inhibition of mitochondrial respiration [33]. Similarly, the osteogenic differentiation of hBM-MSCs and umbilical cord-derived MSCs is accompanied by mitochondrial biogenesis, characterized by the induction of several mitochondrial biogenesis regulators, increased mtDNA copy number, cristae development, and elevated expression and activity of OXPHOS complexes [37][38][39]. We recently demonstrated increases in PGC-1a expression, the mitochondria to cytoplasm ratio, mtDNA content, and OXPHOS expression and activity during the hepatogenic differentiation of hBMMSCs [40].…”

Mesenchymal Stromal Cells from Female Donors Enhance Breast Cancer Cell Proliferation in vitro

“…The optimal cell culture method remains under debate, but in none of the previous co-culture reports of BCCs and MSCs, there are any preceding attempts to systemically evaluate the donor effect of MSCs in such large numbers as now. Since there is a vast heterogeneity in the source of MSCs due to the individual donors [20] and different sites for collecting MSCs [33], it is of the utmost importance to study MSCs in cancer so that the properties of MSCs from different sites and donors are taken into account. It has been reported previously that MSCs express a wide array of growth factors and cytokines [34] both when cultured alone and in co-culture with cancer cells.…”

“…Conflicting in vitro data also exist on the effect of MSCs on tumor cell proliferation, morphology and adhesion [17,18,19]. This contradiction may be partly due to the variability in the source of MSCs, and furthermore donor-dependent variability cannot be excluded [20]. …”