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BJOG. 2019 Dec 25. doi: 10.1111/1471-0528.16078. [Epub ahead of print]

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

Author information

1
Fundación Instituto Valenciano de Infertilidad (FIVI), Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
2
Data Science, Biostatistics and Bioinformatics, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
3
Igenomix Academy, Valencia, Spain.
4
IVIRMA, Barcelona, Barcelona, Spain.
5
IVIRMA Valencia, Valencia, Spain.
6
Reproductive Medicine Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.

Abstract

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

PMID:
31876085
DOI:
10.1111/1471-0528.16078

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