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

BJOG. 2020 Apr;127(5):551-560. doi: 10.1111/1471-0528.16078. Epub 2020 Jan 19.


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: Fundación-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.

Keywords: Asherman's syndrome; bone marrow-derived stem cells; endometrial atrophy; endometrial regeneration; paracrine mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen / metabolism
  • Animals
  • Atrophy / therapy*
  • Cyclin D1 / metabolism
  • Cytokines / metabolism
  • Down-Regulation
  • Endometrium / pathology*
  • Endometrium / physiology*
  • Female
  • Gynatresia / therapy*
  • Humans
  • Interleukin-8 / metabolism
  • Leukocyte Elastase / metabolism
  • Models, Animal
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism
  • Regeneration*
  • Retrospective Studies
  • Stem Cell Transplantation*
  • Transplantation, Autologous
  • Up-Regulation
  • Uterus / metabolism


  • AC133 Antigen
  • CXCL8 protein, human
  • Cytokines
  • Interleukin-8
  • JUN protein, human
  • PROM1 protein, human
  • Plasminogen Activator Inhibitor 1
  • Proto-Oncogene Proteins c-jun
  • Cyclin D1
  • Leukocyte Elastase