Dihydrotestosterone induces pro-angiogenic factors and assists homing of MSC into the cardiac tissue

Abstract

The use of mesenchymal stem cells (MSC) as a therapeutic tool in cardiovascular diseases is promising. Since androgens exert some beneficial actions on the cardiovascular system, we tested our hypothesis that this hormone could promote MSC-mediated repair processes, also. Cultured MSCs isolated from Wharton's jelly were exposed to 30 nM dihydrotestosterone (DHT) for 1 or 4 days and the effects of the hormone on their growth/migration/adhesion and the underlying mechanisms were assessed. Results were obtained by real-time cell impedance measurements, and DNA quantification showed that DHT increased MSC proliferation by ~30%. As determined by xCELLigence system, DHT augmented (~2 folds) the migration of MSC toward cardiac tissue slices (at 12 h), and this effect was blocked by flutamide, an androgen receptor (AR) antagonist. Exposure of cells to DHT, upregulated the gene and protein expression of , and and downregulated the expression of DHT significantly induced the release of nitric oxide by MSC (≥2-fold) and flutamide blocked this effect. When MSCs were co-cultured with cardiac slices, immunohistochemical analysis and qRT-PCR showed that the integration of DHT-stimulated MSC was significantly higher than that of in controls. In conclusion, our findings provide the first evidence that DHT promotes MSC growth, migration and integration into the cardiac slices. The modulating effects of DHT were associated with upregulation of ARs and of key molecules known to promote tissue remodeling and angiogenesis. Our findings suggest that priming of MSC with DHT may potentially increase their capability to regenerate cardiac tissue; studies are needed to confirm our findings.

Dihydrotestosterone Augments the Angiogenic and Migratory Potential of Human Endothelial Progenitor Cells by an Androgen Receptor-Dependent Mechanism

“…One can safely assume that the increase in proteolytic activity is a precursor for the removal of damaged scar tissue. The data are consistent with the results of our previous experiments on human Wharton's Jelly-derived mesenchymal stromal cells (MSCs) [26], except that, in the present experiments, the DHT-induced increase in MMP-2 mRNA was not accompanied by enhanced protein expression in EPCs. It has been reported that the formation and activity of MMPs are controlled at several steps, such as genetic transcription and the conversion of latent enzymes into active forms; therefore, the lack of correlation between MMP-2 mRNA expression and protein levels is not an uncommon phenomenon [27].…”

Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies

“… [ 157 ] DHT Wharton’s jelly – In vitro Increased proliferation; upregulated cell migration and pro-angiogenic factors, such as MMP-9, VEGF, and angiogenin. [ 156 ] Oxytocin Bone marrow (diabetic rat) Myocardial infarction In vitro / in vivo (rats) Restored secretion of KLF2; increased angiogenesis in vitro; improved cardiac function and reduced fibrosis in vivo. [ 159 ] Melatonin Bone marrow (rat) Osteoporosis and colitis model In vitro / in vivo (rats) Preserved self-renewal and differentiation capacity after long-term passaging; preserved therapeutic potential of long-term passaged MSC in bone regeneration and immunotherapy in vivo.…”

“…The hormone dihydrotestosterone (DHT) stimulates MSC proliferation, migration, and tissue engraftment. In addition, DHT-primed MSC contribute to cardiac regeneration [ 156 ]. Other studies have explored the effects of Apelin-13 peptide priming on MSC differentiation, proliferation, and survival in ischemic models.…”

Targeting angiogenesis in myocardial infarction: Novel therapeutics (Review)

“…Hormones also promote myocardial repair after infarction. Dihydrotestosterone induces angiogenic factors and helps to nest MSCs into heart tissue (92). Furthermore, irisin plays an anti-MI role by promoting angiogenesis (93).…”