Bone marrow‐derived progenitor cells contribute to remodeling of the postpartum uterus

• Published in: Stem cells (Dayton, Ohio) Ohio), 2021-11, Vol.39 (11), p.1489-1505
• Main Authors: Tal, Reshef, Kisa, Jacqueline, Abuwala, Nafeesa, Kliman, Harvey J., Shaikh, Shafiq, Chen, Alice Y., Lyu, Fang, Taylor, Hugh S.
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Animals; Apoptosis; Blood vessels; Bone marrow; Bone Marrow - metabolism; Bone Marrow Cells - metabolism; Bone Marrow Transplantation; CD45 antigen; Cell proliferation; Cytokeratin; Endometrium; Endothelial cells; Endothelial Cells - metabolism; Endothelium; Epithelial cells; Epithelium; Female; Flow cytometry; Fluorescence; Green fluorescent protein; Green Fluorescent Proteins - metabolism; Humans; Immunofluorescence; Leukocytes; Macrophages; Mice; Mice, Inbred C57BL; Osteoprogenitor cells; Postpartum; Postpartum Period; Progenitor cells; Regeneration; remodeling; Senescence; stem cells; Stem Cells - metabolism; Tissue engineering; Uterus; Uterus - metabolism
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.3431

Endometrial stem/progenitor cells play a role in postpartum uterine tissue regeneration, but the underlying mechanisms are poorly understood. While circulating bone marrow (BM)‐derived cells (BMDCs) contribute to nonhematopoietic endometrial cells, the contribution of BMDCs to postpartum uterus remodeling is unknown. We investigated the contribution of BMDCs to the postpartum uterus using 5‐fluorouracil‐based nongonadotoxic BM transplant from green fluorescent protein (GFP) donors into wild‐type C57BL/6J female mice. Flow cytometry showed an influx of GFP+ cells to the uterus immediately postpartum accounting for 28.7% of total uterine cells, followed by a rapid decrease to prepregnancy levels. The majority of uterine GFP+ cells were CD45+ leukocytes, and the proportion of nonhematopoietic CD45−GFP+ cells peaked on postpartum day (PPD) 1 (17.5%). Immunofluorescence colocalization of GFP with CD45 pan‐leukocyte and F4/80 macrophage markers corroborated these findings. GFP+ cells were found mostly in subepithelial stromal location. Importantly, GFP+ cytokeratin‐positive epithelial cells were found within the luminal epithelium exclusively on PPD1, demonstrating direct contribution to postpartum re‐epithelialization. A subset (3.2%) of GFP+ cells were CD31+CD45− endothelial cells, and found integrated within blood vessel endothelium. Notably, BM‐derived GFP+ cells demonstrated preferential proliferation (PCNA+) and apoptosis (TUNEL+) on PPD1 vs resident GFP− cells, suggesting an active role for BMDCs in rapid tissue turnover. Moreover, GFP+ cells gradually acquired cell senescence together with decreased proliferation throughout the postpartum. In conclusion, BM‐derived progenitors were found to have a novel nonhematopoietic cellular contribution to postpartum uterus remodeling. This contribution may have an important functional role in physiological as well as pathological postpartum endometrial regeneration. Bone marrow‐derived stem cells (BMDSCs) are mobilized to the circulation and get recruited to the uterus in the postpartum period where they contribute to various nonhematopoietic endometrial cell populations as part of the process of cellular turnover and regeneration. They differentiate into stromal cells, endothelial cells (EC), and epithelial cells, actively participating in uterine tissue remodeling.