PubMed · 15190688
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2004. Possible replacement for artificial breast implants.. https://pubmed.ncbi.nlm.nih.gov/15190688/
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We previously demonstrated that maternal protein restriction (MPR) during pregnancy and lactation led to fetal growth restriction and development of increased visceral adiposity in adult male rat offspring. Here we studied the rate of proliferation and differentiation of adipocyte precursors (preadipocytes) in vitro to investigate whether MPR may permanently program adipocyte growth and development in adult male offspring. Preadipocytes were isolated from visceral adipose tissue of control and MPR offspring at 130 days of age, and cultured under standard conditions. The rate of proliferation was studied by [(3)H]-thymidine incorporation, and the rate of differentiation assessed with the use of biochemical and morphological markers. Although it did not affect the rate of differentiation, MPR increased the rate of preadipocyte proliferation by almost twofold. To ascertain if the increased proliferation was due to persisting in vivo influences or aberrations inherent in the precursor cells, we studied the rate of preadipocyte proliferation in subcultures. We found that the increased rate of proliferation of MPR preadipocytes persisted throughout the first two subcultures, indicative of an inherent abnormality. In addition, we examined the rate of preadipocyte proliferation under reduced serum conditions. We showed that MPR reduced the rate of preadipocyte proliferation to 56 and 35% of the control in the presence of 5 and 2.5% serum, respectively. Taken together, these results demonstrate that MPR permanently programs adipocyte growth and development such that adipocyte precursors derived from MPR offspring replicate excessively under standard culture conditions but exhibit markedly attenuated growth rate under reduced serum conditions.
Micro-environment seems to exert an important influence on human mesenchymal stem cell (MSC) differentiation and proliferative capacity in bone marrow as well as in culture ex vivo. Oct-4, Rex-1, and TERT genes are well-known for the maintenance of pluripotentiality differentiation and the proliferative capacity of embryonic stem cells. Some previous data report expression of these embryonic factors in selected clones from bone marrow adult stem cells. Our goal was to study expression of Oct-4, Rex-1, and TERT in primary cultured human MSC according to the serum concentration. In addition, we have studied the expression of Gata-4 since this factor plays a key role in organogenesis. We hypothesized that low serum concentration with appropriate growth factors may induce an undifferentiated status with a re-expression of embryonic factors and extend differentiation capacity. Thus, using a defined culture medium, we report on the increased expression of Oct-4, Rex-1, and Gata-4 in human MSC. We have correlated this expression to an increase in differentiation efficiency towards osteogenic and adipogenic phenotypes. Our data suggest that the culture medium used permits the emergence of adult stem cells with a high differentiation capacity and expression of embryonic factors. These cells may have important implications for cell therapy.
Osteoblasts and adipocytes are thought to derive from a common bone marrow stromal cell (BMSC) precursor. Activation of the canonical Wnt signaling pathway plays a pivotal role in the differentiation of BMSCs along either of these two lineages, promoting osteogenesis and inhibiting adipogenesis. Liganded nuclear receptors, including the vitamin D receptor (VDR) and peroxisomal proliferator-activated receptor gamma (PPARgamma), can also affect BMSCs differentiation. To address whether VDR ablation modulates the differentiation of BMSCs into the osteoblast or adipogenic lineages, BMSCs were isolated from VDR null mice and from their wild-type littermates. VDR ablation did not alter osteoblastic differentiation. However, when cultured under adipogenic conditions, BMSCs from the VDR null mice expressed higher mRNA levels of PPARgamma and of markers of adipogenic differentiation. An increase in the size and number of mature adipocyte foci was also observed in cultures isolated from VDR null mice relative to those isolated from wild-type mice. To address whether the increased adipogenesis observed in the VDR null cultures was associated with inhibition of the canonical Wnt signaling pathway, mRNA levels for DKK1 and SFRP2 were examined. Cultures from the VDR null mice expressed higher levels of mRNA encoding DKK1 and SFRP2 than did the wild-type cultures. This difference is, at least in part, due to ligand-dependent actions of the VDR, since 1,25-dihydroxyvitamin D3 suppressed DKK1 and SFRP2 expression in wild-type cultures. Thus, the VDR inhibits adipogenesis of BMSCs at least in part by suppressing the expression of inhibitors of the canonical Wnt signaling pathway.