Novel therapeutic strategies for injured endometrium: Autologous intrauterine transplantation of menstrual blood-derived cells from infertile patients

Background Menstrual blood-derived cells show regenerative potential as a mesenchymal stem cell and may therefore be a novel stem cell source of treatment for refractory infertility with injured endometrium. However, there have been few pre-clinical studies using cells from infertile patients, which needs to be addressed before establishing an autologous transplantation. Herein, we aimed to investigate the therapeutic capacity of menstrual blood-derived cells from infertile patients on endometrial infertility. Methods We collected menstrual blood-derived cells from volunteers and infertile patients, and confirmed their mesenchymal stem cell phenotype by flowcytometry and induction of tri-lineage differentiation. We compared the proliferative and paracrine capacities of these cells. Furthermore, we also investigated the regenerative potential and safety concerns of the intrauterine transplantation of infertile patient-derived cells using a mouse model with mechanically injured endometrium. Results Menstrual blood-derived cells from both infertile patients and volunteers showed phenotypic characteristics of mesenchymal stem cells. In vitro proliferative and paracrine capacities for wound healing and angiogenesis were equal for both samples. Furthermore, the transplantation of infertile patient-derived cells into uterine horns of the mouse model ameliorated endometrial thickness, prevented fibrosis and improved fertility outcomes without any apparent complications. Conclusions In our preclinical study, intrauterine transplantation of menstrual blood-derived cells may be a novel and attractive stem cell source for the curative and prophylactic therapy for injured endometrium. Further studies will be warranted for future clinical application. ### Competing Interest Statement AU is a co-researcher with MTI Ltd., Terumo Corp., BONAC Corp., Kaneka Corp., CellSeed Inc., ROHTO Pharmaceutical Ltd., SEKISUI MEDICAL Ltd., Metcela Inc., PhoenixBio Ltd., Dai Nippon Printing Ltd. AU is a stockholder of TMU Science Ltd., Morikuni Ltd., and Japan Tissue Engineering Ltd. The other authors declare that there is no conflict of interest regarding the work described herein. * MSCs : Mesenchymal stem cells MenSCs : menstrual blood-derived stem cells DMEM : Dulbecco’s modified Eagle’s medium FBS : fetal bovine serum AA : penicillin-streptomycin amphotericin B suspension PBS : phosphate-buffered saline PS : penicillin streptomycin ISCT : international society for cellular therapy FABP-4 : fatty acid binding protein-4 PFA : paraformaldehyde IgG : immunoglobulin G HRP : horseradish peroxidase DAB : diaminobenzidine CM : conditioned media BSA : bovine serum albumin LS-MS : liquid chromatography tandem mass spectrometry HPLC : high-performance liquid chromatography HUVECs : human umbilical vein endothelial cells ECM : endothelial cell medium GFR : growth factor reduce H&E : hematoxylin and eosin MT : masson trichrome RT-qPCR : real-time quantitative polymerase chain reaction VEGF : vascular endothelial growth factor FGF : fibroblast growth factor EGF : epidermal growth factor GAPDH : glyceraldehyde-3-phosphate dehydrogenase SEM : standard error of the mean SD : standard deviation