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    • Many immunity associated genes previously linked to MSCs

    2018-10-22

    Many immunity-associated genes previously linked to MSCs were also expressed by all 3 cell populations, particularly by bmMSC. A comparison of the functional capacity of each population to influence lymphocytic proliferation suggested significant differences between the three sources of cells, with cCFU-F showing little activity. This has also been observed in a previous study of MSC-derived populations from foetal heart (Jiang et al., 2006), although the converse has also been reported (Hoogduijn et al., 2007). We re-examined the cell surface immunophenotype of these three populations in order to identify an underlying mechanism for such functional variability. All three populations showed high percentages of PR-619 positive for CD81, the relative mean intensity of this epitope on cCFU-F was dramatically lower than in either of the other populations. CD81 (TAPA-1) is a member of the transmembrane 4 superfamily whose loss has been associated with enhanced T-cell proliferation (Miyazaki et al., 1997). It has been proposed that MSCs mediate their humoral properties via the secretion of membrane-bound exosomes that contain a variety of chemokines and have been reported to contain CD81 (Lai et al., 2010). The delivery of such exosomes can reduce infarct size in animal models (Lai et al., 2010), suggesting a potential role for CD81 in immunosuppression. Hence, reduced CD81 may at least in part explain the reduced immunosuppressive capacity of the cCFU-F population. Several studies (Riekstina et al., 2009; Greco et al., 2007; Barraud et al., 2007; Lengner et al., 2007) have reported the expression of embryonic stem (ES) cell markers on MSC derived from bone marrow, adipose, dermal and heart. Knockdown of Oct4 in MSCs removes them from the cell cycle, as may be the role for this protein in ES cells. However, not all studies show Oct4 expression in MSC and our data suggests no/negligible expression of this gene. However, we did observe expression of a large number of Plurinet genes in these MSC populations. This may indicate a closer alignment to the ‘attractor state’ of pluri/multipotency than other adult cell populations. Indeed MSCs from a variety of sources are more readily reprogrammed to a pluripotent state than fibroblasts (Yan et al., 2009; Cai et al., 2010). The proposed association between organ-specific MSC populations and the pericytic/perivascular compartment agrees with literature from over 50years ago addressing the potency and plasticity of pericytes and their related lineages (Tilton, 1991). MSCs and pericytes likely share a common phylogenetic and possibly ontological relationship being descendant of distinct vascular beds both during embryo development but also in the adult (Yamashita et al., 2000), and in the vasculature of tumours (Bexell et al., 2009). It has been suggested that within the perivascular environment, a continuum exists between fibroblasts, myofibroblasts and vascular smooth muscle cells and that pericytes and MSC-like populations are closely related and located adjacent to the vascular endothelium throughout the organs of the body. In humans, both MSC and pericytes express CD146, CD140b, CD271 and NG2 suggesting considerable commonality between these cell types (Crisan et al., 2008; da Silva Meirelles et al., 2008; Covas et al., 2008; Sundberg et al., 2002; Brachvogel et al., 2005). In support of this, we found gene and/or protein expression of CD146, CD140b, 훼SMA, Cspg4/NG2, CD24, Annexin A5, and Desmin in each of our 3 MSC-like populations. The relative level of each marker did vary, potentially indicating differences in the cell of origin or position along a lineage continuum of each population, the latter again potentially being affected by population heterogeneity. Analysis of the most compartment-specific genes for each population particularly supported this hypothesis for the kCFU-F with enriched expression of Myh11, Mylk, Mcam (CD146), Efnb2, Edn1, Angpt2 and Vegfc (Supplementary Table 7C), all of which are associated with vascular, lymphatic or perivascular smooth muscle development. In addition, both kCFU-F and cCFU-F differentially expressed Crim1, a transmembrane regulator of VEGF activity that is known to be expressed in the perivascular musculature of large arteries (Pennisi et al., 2007). The stronger link with this ontogeny and MSC-like fractions isolated from solid organs may be of significance.