Human umbilical cord perivascular cells maintain regenerative traits following exposure to cyclophosphamide

• Published in: Cancer letters 2021-03, Vol.501, p.133-146
• Main Authors: Zohni, Khaled, Lopez, Lianet, Mander, Poonam, Szaraz, Peter, Filice, Melissa, Wyse, Brandon A., Garcia, Meredith, Gat, Itai, Glass, Karen, Gauthier-Fisher, Andrée, Librach, Clifford L.
• Format: Article
• Language: English
• Subjects: Animal models; Bone marrow; Cell differentiation; Cell lineage; Chemotherapy; Chemotoxicity; Collagen; Cyclophosphamide; Cytotoxicity; Failure; Fertility; Fertility preservation; Gene expression; Immunogenicity; Infertility; Mesenchymal stromal cell; Mesenchyme; MSC; Ovaries; Paracrine signalling; Population; Stromal cells; Umbilical cord
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2020.12.035

Chemotherapies can cause germ cell depletion and gonadal failure. When injected post-chemotherapy, mesenchymal stromal cells (MSCs) from various sources have been shown to have regenerative effects in rodent models of chemotherapy-induced gonadal injury. Here, we evaluated two properties of a novel source of MSC, first trimester (FTM) human umbilical cord perivascular cells (HUCPVCs) (with increased regenerative potential compared to older sources), that may render them a promising candidate for chemotherapeutic gonadal injury prevention. Firstly, their ability to resist the cytotoxic effects of cyclophosphamide (CTX) in vitro, as compared to term HUCPVCs and bone marrow cells (BMSCs); and secondly, whether they prevent gonadal dysfunction if delivered prior to gonadotoxic therapy in vivo. BMSC, FTM HUCPVC, term HUCPVC, and control NTERA2 cells were treated with moderate (150 μmol/L) and high (300 μmol/L) doses of CTX in vitro. Viability, proliferative capacity, mesenchymal cell lineage markers and differentiation capacity, immunogenicity, and paracrine gene expression were assessed. CTX was administered to Wistar rats 2 days following an intra-ovarian injection of FTM HUCPVC. HUCPVC survival and ovarian follicle numbers were assessed using histological methods. We conclude that FTM HUCPVC maintain key regenerative properties following chemotherapy exposure and that pre-treatment with these cells may prevent CTX-induced ovarian damage in vivo. Therefore, HUCPVCs are promising candidates for fertility preservation. •HUCPVC survive and maintain ability to proliferate and differentiate towards MSC lineages when treated with cyclophophasmide in vitro.•Cyclophosphamide treatment in vitro does not alter the low immunogenicity and paracrine properties of HUCPVC.•Intra-ovarian administration of HUCPVC prior to chemotherapy prevents primordial follicle loss.