Stem cell paracrine actions in tissue regeneration and its potential therapeutic effect in human endometrium: a retrospective study

OBJECTIVE: Determining genetic and paracrine mechanisms behind endometrial regeneration in Asherman's syndrome and endometrial atrophy (AS/EA) patients after autologous CD133(+) bone marrow-derived stem cell (CD133(+) BMDSC) transplantation. DESIGN: Retrospective study using human endometrial biopsies and mouse models. SETTING: Fundacion-IVI, IIS-La Fe, Valencia, Spain. SAMPLES: Endometrial biopsies collected before and after CD133(+) BMDSC therapy, from eight women with AS/EA (NCT02144987) from the uterus of five mice with only left horns receiving CD133(+) BMDSC therapy. METHODS: In human samples, haematoxylin and eosin (H&E) staining, RNA arrays, PCR validation, and neutrophil elastase (NE) immunohistochemistry (IHQ). In mouse samples, PCR validation and protein immunoarrays. MAIN OUTCOME MEASURES: H&E microscopic evaluation, RNA expression levels, PCR, and growth/angiogenic factors quantification, NE IHQ signal. RESULTS: Treatment improved endometrial morphology and thickness for all patients. In human samples, Jun, Serpine1, and Il4 were up-regulated whereas Ccnd1 and Cxcl8 were down-regulated after treatment. The significant decrease of NE signal corroborated Cxcl8 expression. Animal model analysis confirmed human results and revealed a higher expression of pro-angiogenic cytokines (IL18, HGF, MCP-1, MIP2) in treated uterine horns. CONCLUSIONS: CD133(+) BMDSC seems to activate several factors through a paracrine mechanism to help tissue regeneration, modifying endometrial behaviour through an immunomodulatory milieu that precedes proliferation and angiogenic processes. Insight into these processes could bring us one step closer to a non-invasive treatment for AS/EA patients. TWEETABLE ABSTRACT: CD133(+) BMDSC therapy regenerates endometrium, modifying the immunological milieu that precedes proliferation and angiogenesis.