Abstract
Therapeutic use of mesenchymal stem cells (MSCs) for tissue repair has great potential. MSCs from multiple sources, including those derived from human umbilical matrix, namely Wharton’s jelly, may serve as a resource for obtaining MSCs. However, low in vivo engraftment efficacy of MSCs remains a challenging limitation. To improve clinical outcomes using MSCs, an in-depth understanding of the mechanisms and factors involved in successful engraftment is required. We recently demonstrated that 17β-estradiol (E2) improves MSCs in vitro proliferation, directed migration and engraftment in murine heart slices. Here, using a proteomics approach, we investigated the angiogenic potential of MSCs in vivo and the modulatory actions of E2 on mechanisms involved in tissue repair. Specifically, using a Matrigel® plug assay, we evaluated the effects of E2 on MSCs-induced angiogenesis in ovariectomized (OVX) mice. Moreover, using proteomics we investigated the potential pro-repair processes, pathways, and co-mechanisms possibly modified by the treatment of MSCs with E2. Using RT-qPCR, we evaluated mRNA expression of pro-angiogenic molecules, including endoglin, Tie-2, ANG, and VEGF. Hemoglobin levels, a marker for blood vessel formation, were increased in plugs treated with E2 + MSCs, suggesting increased capillary formation. This conclusion was confirmed by the histological analysis of capillary numbers in the Matrigel® plugs treated with E2 + MSC. The LC-MS screening of proteins obtained from the excised Matrigel® plugs revealed 71 proteins that were significantly altered following E2 exposure, 57 up-regulated proteins and 14 down-regulated proteins. A major result was the association of over 100 microRNA molecules (miRNAs) involved in cellular communication, vesicle transport, and metabolic and energy processes, and the high percentage of approximately 25% of genes involved in unknown biological processes. Together, these data provide evidence for increased angiogenesis by MSCs treated with the sex hormone E2. In conclusion, E2 treatment may increase the engraftment and repair potential of MSCs into tissue, and may promote MSC-induced angiogenesis after tissue injury.
Highlights
Cardiovascular disease is the leading cause of mortality and morbidity in women [1]
We have previously shown the pro-angiogenic and tissue regeneration potential of E2-treated mesenchymal stem cells (MSCs) in vitro; the current study was focused on the in vivo analysis of E2stimulated MSCs secretome by using Nano Liquid Chromatography—Mass Spectrometry analyses
We evaluated the pro-angiogenic, or tissue regeneration, potential induced by E2 on MSCs using the in vivo Matrigel® plug assay
Summary
Cardiovascular disease is the leading cause of mortality and morbidity in women [1]. multiple therapeutic approaches, including changes in life style, drugs, and surgery, are available to treat/manage various heart conditions, heart transplantation remains the only option for patients with severely advanced heart disease. Use of bone marrow derived MSCs for tissue repair/regeneration has been extensively studied and considered a gold standard for multiple clinical applications of MSCs [3]. Based on basic and clinical findings over the last decade, it has become increasingly clear that bone marrow may not be the most appropriate source for the collection of MSCs. Apart from the invasive and painful isolation procedure, the cell density of MSCs in bone aspirates is markedly low (approximately 0.001–0.01%) [3,4]. Apart from the invasive and painful isolation procedure, the cell density of MSCs in bone aspirates is markedly low (approximately 0.001–0.01%) [3,4] Their qualitative and quantitative properties decrease with the donor’s age [4]. WJ-MSCs, called umbilical matrix-derived cells, have exceptional properties and are bonafide MSCs [8]
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