Epigenetics, ovarian cell plasticity, and platelet-rich plasma: Mechanistic theories

Abstract

Ovarian platelet-rich plasma (PRP) is claimed to restore fertility potential by improving reserve, an effect perhaps mediated epigenetically by platelet-discharged regulatory elements rather than gonadotropin activated G-protein coupled receptors, as with stimulated in vitro fertilization (IVF). The finding that fresh activated platelet releaseate includes factors able to promote developmental signaling networks necessary to enable cell pluripotency tends to support this theory. The mechanistic uncertainty of intraovarian PRP notwithstanding, at least two other major challenges confront this controversial intervention. First is to clarify how perimenopausal ovarian function is reset to levels consistent with ovulation. Perhaps a less obvious secondary problem is to confine this renewal such that any induced recalibration of cellular plasticity is kept within acceptable physiologic bounds. Thus, any ‘drive’ to ovarian rejuvenation must incorporate both accelerator and brake. Ovarian aging may be best viewed as a safeguard against pathologic overgrowth, where senescence operates as an evolved tumor-suppression response. While most ovary cells reach the close of their metabolic lifespan with low risk for hypertrophy, enhanced lysosomal activity and the pro-inflammatory ‘Senescence Associated Secretory Phenotype’ usually offsets this advantage over time. But is recovery of ovarian fitness possible, even if only briefly prior to IVF? Alterations in gap junctions, bio-conductive features, and modulation of gene regulatory networks after PRP use in other tissues are discussed here alongside early data reported from reproductive medicine.

Intrathecal Autologous Thrombin-Activated Condensed Platelet Cytokines in Chronic Neurodegenerative Disease: Anti-inflammatory and Regenerative Responses, Phase I

“…Most PRP applications tend to support tissue regeneration, although some authors are more reserved [79,80]. Notwithstanding the growing interest in PRP and its derivatives in new domains [81], nonuniform sample preparations [82,83] have made randomized controlled trials difficult to standardize and almost impossible to interpret. While any diffuse hyperinflammation corrected by PLT cytokine use is welcome, numerous CNS signal pathways are impacted upon PLT activation to facilitate tissue repair, angiogenesis and neurogenesis [84].…”

Multichannel Recovery Potential with Activated Autologous Intraovarian Platelet-Rich Plasma and Its Derivatives

“…When mice are experimentally rendered infertile by cyclophosphamide, treatment with conditioned medium and PRP was able to boost expression of ‘mothers against decapentaplegic’ homologs 1 and 2 (SMAD1, SMAD2), growth differentiation factor-9 (GDF9), and bone morphogenetic protein-15 (BMP15) [ 63 ]. Although synergy may be inferred with PRP and conditioned medium, PRP carries its own cytokines, including platelet derived growth factor (PDGF), GDF9, and TGF-β [ 64 , 65 ]. For human granulosa cells, TGF-β1 upregulates gap junction alpha-1 protein/connexin 43 (Cx43) to amplify intercellular communication specifically involving activin receptor-like kinase (ALK) 5-mediated SMAD-related proteins [ 66 ].…”

mTOR Inhibition via Low-Dose, Pulsed Rapamycin with Intraovarian Condensed Platelet Cytokines: An Individualized Protocol to Recover Diminished Reserve?

“…Notwithstanding its use in organ transplantation, which succeeds best with minimal inflammation, rapamycin also paradoxically increases some pro-inflammatory cytokine outputs (i.e., IL-6, IL-12, IL-23) while lowering production of the anti-inflammatory IL-10 [54]. Such actions would not be welcome if rapamycin were planned for simultaneous use with conventional intraovarian PRP, which by design places PLT boluses beneath the surface epithelium [55]. That PLTs exposed to rapamycin undergo functional change is uncontested-a property exploited in vascular stents coated with rapamycin to prevent restenosis [56].…”