Abstract
Clinical trials evaluating cardiac progenitor cells (CPC) demonstrated feasibility and safety, but no clear functional benefits. Therefore a deeper understanding of CPC biology is warranted to inform strategies capable to enhance their therapeutic potential. Here we have defined, using a label-free proteomic approach, the differential cytoplasmic and nuclear compartments of human CPC (hCPC). Global analysis of cytoplasmic repertoire in hCPC suggested an important hypoxia response capacity and active collagen metabolism. In addition, comparative analysis of the nuclear protein compartment identified a significant regulation of a small number of proteins in hCPC versus human mesenchymal stem cells (hMSC). Two proteins significantly upregulated in the hCPC nuclear compartment, IL1A and IMP3, showed also a parallel increase in mRNA expression in hCPC versus hMSC, and were studied further. IL1A, subjected to an important post-transcriptional regulation, was demonstrated to act as a dual-function cytokine with a plausible role in apoptosis regulation. The knockdown of the mRNA binding protein (IMP3) did not negatively impact hCPC viability, but reduced their proliferation and migration capacity. Analysis of a panel of putative candidate genes identified HMGA2 and PTPRF as IMP3 targets in hCPC. Therefore, they are potentially involved in hCPC proliferation/migration regulation.
Highlights
Clinical trials evaluating cardiac progenitor cells (CPC) demonstrated feasibility and safety, but no clear functional benefits
Among the cytoplasmic proteins expressed more differentially in human CPC (hCPC), we identified 11 upregulated proteins, including 3’-phosphoadenosine 5’-phosphosulfate synthase 2 (PAPSS2), procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1) and prolyl 4-hydroxylase, alpha polypeptide I/II, (P4HA1 and P4HA2) (Fig. 1b)
We identified 5 moderately downregulated proteins in hCPC, including aspartate beta-hydroxylase (ASPH) and insulin-like growth factor mRNA binding protein 2 (IGFBP2) (Fig. 1c)
Summary
Clinical trials evaluating cardiac progenitor cells (CPC) demonstrated feasibility and safety, but no clear functional benefits. In spite of the recent c ontroversy[13,14,15] several important cues have been provided during the last years, and main technical limitations at the origin of the conflict have been mostly clarified[16,17,18] Results using these mouse lines (c-Kit-Cre/Rosa26-floxed-STOP-reporters)[14,15] or dual-recombinase a pproaches[13], concluded that cardiac c-Kit+ populations have a marginal cardiomyogenic capacity (0.01% of total cardiomyocytes). Compelling experiments concluded that c-kit haploinsufficiency in all these genetic fate-mapping experiments is at the most probable origin of all discrepancies, provoking growth and clonogenesis, cardiosphere formation defects All these deficits, including the cardiomyogenic differentiation capacity were completely rescued by BAC transfection, that harbors the complete cloned c-Kit locus, and, Vicinanza et al confirmed the described phenotypes in vivo, using cloned cardiac c-kit+lowCD45-CD31- cells[17]. The recent identification of c-Kit+ stem cells in adult vessels[20] and the characterization of human cardiac atrial myxomas as the first-described CSC (c-Kit+CD45-CD31-)-related human heart d isease[21], clearly offer indirect support for c kit+ CSC
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