Abstract
Human mesenchymal stromal cell (hMSC) secretomes have shown to influence the microenvironment upon injury, promoting cytoprotection, angiogenesis, and tissue repair. The angiogenic potential is of particular interest for the treatment of ischemic diseases. Interestingly, hMSC secretomes isolated from different tissue sources have shown dissimilarities with respect to their angiogenic profile. This study compares angiogenesis of hMSC secretomes from adipose tissue (hADSCs), bone marrow (hBMSCs), and umbilical cord Wharton’s jelly (hWJSCs). hMSC secretomes were obtained under xenofree conditions and analyzed by liquid chromatography tandem mass spectrometry (LC/MS-MS). Biological processes related to angiogenesis were found to be enriched in the proteomic profile of hMSC secretomes. hWJSC secretomes revealed a more complete angiogenic network with higher concentrations of angiogenesis related proteins, followed by hBMSC secretomes. hADSC secretomes lacked central angiogenic proteins and expressed most detected proteins to a significantly lower level. In vivo all secretomes induced vascularization of subcutaneously implanted Matrigel plugs in mice. Differences in secretome composition were functionally analyzed with monocyte and endothelial cell (EC) in vitro co-culture experiments using vi-SNE based multidimensional flow cytometry data analysis. Functional responses between hBMSC and hWJSC secretomes were comparable, with significantly higher migration of CD14++ CD16− monocytes and enhanced macrophage differentiation compared with hADSC secretomes. Both secretomes also induced a more profound pro-angiogenic phenotype of ECs. These results suggest hWJSCs secretome as the most potent hMSC source for inflammation-mediated angiogenesis induction, while the potency of hADSC secretomes was lowest. This systematic analysis may have implication on the selection of hMSCs for future clinical studies.
Highlights
Mesenchymal stromal cells (MSCs) are a heterogeneous population of non-clonal cells containing a multipotent stem cell fraction
No differences were detected in the differentiation potential of Human mesenchymal stromal cell (hMSC) from different tissue sources. hADSCs showed higher proliferation abilities compared with hBMSCs and hWJSCs (Fig. 1b), with significantly higher cumulative population doublings (p < 0.05; one-way ANOVA with Tukey multiple correction) (Fig. 1c)
The distribution of the recorded events within the t-SNE maps is visualized by cumulative density plots of each cell source (Fig. 1f). hBMSCs appeared to be significantly more abundant in cluster 2 and 3 and significantly less abundant in cluster 1 and 4, compared with hADSCs and hWJSCs (Fig. 1g)
Summary
Mesenchymal stromal cells (MSCs) are a heterogeneous population of non-clonal cells containing a multipotent stem cell fraction. Since their introduction for the use in regenerative medicine, the number of pre-clinical and first clinical studies has continuously increased over the last decades.[1] More than 850 registered human clinicals trials have been performed by September 2018 (ClinicalTrial.gov) and these numbers are expected to further increase in the near future. It has become evident that functional benefits exerted by MSCs upon transplantation are rather due to the release of paracrine factors and biologically relevant molecules to the neighboring diseased or injured tissue.[2,3] The MSC secretome influences the microenvironment upon injury, promoting cytoprotection, and tissue repair of the damaged area. These effects are of particular interest for the treatment of ischemically damaged tissues in which promoting vascularization and reinstalling perfusion via angiogenesis is crucial for increasing potential tissue rescue and thereby preventing fibrosis
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