Pathways and factors regulated by bone marrow-derived stem cells in human ovarian tissue.

Buigues, A, Diaz-Gimeno, P, Sebastian-Leon, P, Pellegrini, L, Pellicer, N, Pellicer, A, Herraiz, S
Fertil Steril. May. 2021 doi: 10.1016/j.fertnstert.2021.04.009


Objective: To describe molecular and paracrine signaling changes produced by human bone marrow-derived stem cells (BMDSC) in human ovarian cortex. Design: Experimental study. Setting: University hospital research laboratories. Patient(s): Ovarian cortex from poor responder women (n = 7). Animals: Immunodeficient NOD/SCID female mice (n = 18). Intervention(s): Human ovarian cortex strips were xenografted into ovariectomized NOD/SCID female mice. A week later, mice were infused with phosphate-buffered saline, 1 × 106 BMDSC, or 3 × 105 CD133+ cells via tail vein. Gene expression changes and enriched pathways were assessed by RT2 Profiler Arrays. Several upregulated genes were validated in individual samples by real-time quantitative PCR, and transcriptomic results were reinforced by a proteomic assessment. Main outcome measure(s): Gene expression changes, enriched Kyoto Encyclopedia of Genes and Genomes pathways, and paracrine factors. Result(s): Seventy-four Kyoto Encyclopedia of Genes and Genomes pathways were upregulated, with the PI3K-Akt signaling pathway the most enriched after BMDSC and CD133 treatments. The greatest transcriptomic changes were seen on day 14 in the BMDSC group, affecting the regulation of paracrine factors such as KITLG, THBS1, SERPINF1, and TIMP2. Proteomics data verified changes in FoxO signaling, actin cytoskeleton remodeling, and apoptosis by BMDSC. Conclusion(s): We identified paracrine factors and pathways regulated by BMDSC that may be future targets of treatment for the increasing number of poor responder women. Our findings suggest that BMDSC upregulated soluble factors such as KITLG, THBS1, SERPINF1, and TIMP2 as well as PI3K-Akt signaling and regulation of actin cytoskeleton pathways. The identification of these putative underlying mechanisms informs future experiments aiming to optimizing clinical application of BMDSC.