Contribution of Bone Marrow-Derived Stem Cells to Endometrium and Endometriosis
Abstract
Bone marrow-derived cells (BMDCs) can differentiate into nonhematopoietic cells, suggesting that BMDCs may contribute to the maintenance of multiple tissues. Donor-derived bone marrow cells have been identified in human uterine endometrium. Here, two murine models were used to investigate the contribution of nonendometrial stem cells to endometrium. We investigate whether BMDCs can localize to uterine endometrium and to endometriosis. After bone marrow transplantation, male donor-derived bone marrow cells were found in the uterine endometrium of female mice. Although uncommon (<0.01%), these cells can differentiate into epithelial cells. After generation of experimental endometriosis by ectopic endometrial implantation in the peritoneal cavity, bone marrow from LacZ transgenic mice was used for transplantation. LacZ expressing cells were found in the wild-type ectopic endometrium implanted in the peritoneal cavity of hysterectomized LacZ transgenic mice. The repopulation of endometrium with bone marrow-derived stem cells may be important to normal endometrial physiology and also may help to explain the cellular basis for the high long-term failure of conservative alternatives to hysterectomy. The examination of a sexually dimorphic organ such as the uterus demonstrates the ability of male bone marrow, which cannot harbor circulating endometrial cells, to generate endometrium de novo and proves their mesenchymal stem cell origin. Finding Y chromosome bearing endometrial cells demonstrates the potential to recapitulate embryonic developmental pathways that were never activated in males; BMDCs may have vast regenerative capacity. Additionally, the ability of stem cells to engraft endometriosis has implications for the origin and progression of this disease. Ectopic differentiation of stem cells may be a novel mechanism of disease. Disclosure of potential conflicts of interest is found at the end of this article.
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Currently, there are no definitive markers to allow isolation and characterization of endometrial progenitor or stem cells, and it is unknown what drives the recruitment and homing of these cells to eutopic endometrium or ectopic sites.
“Currently, there are no definitive markers to allow isolation and characterization of endometrial progenitor or stem cells, and it is unknown what drives the recruitment and homing of these cells to eutopic endometrium or ectopic sites.107,108”
From Defining Future Directions for Endometriosis Research: Workshop Report From the 2011 World Congress of Endometriosis in Montpellier, France (2013) · cites this paper as [107]
Some mesenchymal/mesothelial cells of the peritoneal cavity, of mesothelial repair after surgery, and in endometrium and endometriosis are directly derived from bone marrow.
“Some of these mesenchymal/ mesothelial cells of the peritoneal cavity (48), of the mesothelial repair after surgery (126) and in endometrium and endometriosis (127-131) are directly derived from bone marrow.”
From Pathogenesis of deep endometriosis (2017) · cites this paper as [128]
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Di Renzo, G. C., Tosto, V., & Giardina, I. (2018) · Best Practice & Research Clinical Obstetrics & Gynaecology · doi:10.1016/j.bpobgyn.2018.01.022 · Cited by 135 · see citing works
Vasculogenesis: A new piece of the endometriosis puzzle
Laschke, M. W., Giebels, C., & Menger, M. D. (2011) · Human Reproduction Update · doi:10.1093/humupd/dmr023 · Cited by 136 · see citing works
“…marrow-derived EPCs CD31+/VEGFR+/CD45–/GFP Bratincsák et al. (2007) Murine endometrium Bone marrow-derived haematopoietic stem cells CD45+, GFP Du and Taylor (2007) Murine endometrium, murine endometriotic lesions Bone marrow-derived stem cells Y chromosome in females, lacZ Ikoma et al.…”
BackgroundCyclical endometrial repair and regeneration
Salamonsen, L. A., Hutchison, J. C., & Gargett, C. E. (2021) · Development · doi:10.1242/dev.199577 · Cited by 133 · see citing works
MicroRNA signature and regulatory functions in the endometrium during normal and disease states
Pan, Q., & Chegini, N. (2008) · Seminars in Reproductive Medicine · doi:10.1055/s-0028-1096128 · Cited by 134 · see citing works
The Role of Stem Cells in the Etiology and Pathophysiology of Endometriosis
Hufnagel, D. H., Li, F., Çoşar, E., Krikun, G., & Taylor, H. S. (2015) · Seminars in Reproductive Medicine · doi:10.1055/s-0035-1564609 · Cited by 132 · see citing works
Self-citationToward the use of endometrial and menstrual blood mesenchymal stem cells for cell-based therapies
Ulrich, D., Muralitharan, R. R., & Gargett, C. E. (2013) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2013.826187 · Cited by 131 · see citing works
“An endogenous source derived from residual fetal stem cells has been proposed [59], while there is some evidence that bone marrow cells may incorporate into human and mouse endometrium and contribute to the generation of endometrial cells [60,61].”
BackgroundMicroRNAs in endometriosis: biological function and emerging biomarker candidates†
Bjorkman, S. H., & Taylor, H. S. (2019) · Biology of Reproduction · doi:10.1093/biolre/ioz014 · Cited by 129 · see citing works
Self-citationEndometriosis: The Role of Iron Overload and Ferroptosis
Ng, S., Norwitz, S. G., Taylor, H. S., & Norwitz, E. R. (2020) · Reproductive Sciences · doi:10.1007/s43032-020-00164-z · Cited by 132 · see citing works
Self-citationEffect of stem cell application on Asherman syndrome, an experimental rat model
Kılıç, S., Yüksel, B., Pınarlı, F. A., Albayrak, A., Özgermen, B. B., & Delibaşı, T. (2014) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-014-0268-2 · Cited by 127 · see citing works
“In another study, after bone marrow transplantation, male donorderived bone marrow cells were found in the uterine endometrium of female mice and some of these cells were found to differentiate into epithelial cells [23].”
BackgroundEffects of Autologous Platelet-Rich Plasma on Regeneration of Damaged Endometrium in Female Rats
Jang, H.-Y., Myoung, S., Choe, J. M., Kim, T., Cheon, Y., Kim, Y. M., & Park, H. (2017) · Yonsei Medical Journal · doi:10.3349/ymj.2017.58.6.1195 · Cited by 126 · see citing works
“1195 tions and effect on endometrial proliferative disorders, such as endometriosis, infections, and invasive process of harvesting.(12,13) Platelet-rich plasma (PRP) is composed of serum containing a platelet concentration of more than 1,000,000 platelets per cubic microliter, which is a rich source of growth factors…”
BackgroundDu, H., Naqvi, H., & Taylor, H. S. (2012) · Stem Cells and Development · doi:10.1089/scd.2011.0193 · Cited by 127 · see citing works
“As previously described [3], Y FISH stain was performed on Formalin-fixed paraffin-embedded specimens tissue were cut into serial 3-mm-thick sections, placed on coated slides, and deparaffinized through a series of xylene and ethanol washes.”
BackgroundMethodInfluentialSelf-citationDonnez, J., Taylor, H. S., Taylor, R. N., Akin, M. D., Tatarchuk, T. F., Wilk, K., Gotteland, J.-P., Lecomte, V., & Bestel, E. (2020) · Fertility and Sterility · doi:10.1016/j.fertnstert.2020.02.114 · Cited by 124 · see citing works
Self-citationCousins, F. L., Murray, A. A., Esnal‐Zufiaurre, A., Gibson, D. A., Critchley, H., & Saunders, P. T. K. (2014) · PLoS ONE · doi:10.1371/journal.pone.0086378 · Cited by 124 · see citing works
“Recent data suggest that mechanisms contributing to endometrial repair may need to be revisited in light of results from studies on human endometrial stem cells [7], circulating progenitor cells [8], and human endometrial side population cells [9], all of which suggest novel role(s) in repair of the tissue following m…”
BackgroundZhao, J., Zhang, Q., Wang, Y., & Li, Y. (2014) · Reproductive Sciences · doi:10.1177/1933719114537715 · Cited by 122 · see citing works
“Recently, Du et al found that the bone marrow-derived cells (BMDCs) can localize to uterine endometrium, and BMDCs contribute to endometrium in 2 murine models.(5,9) So far, there has been no report evaluating the therapeutic effect of BMSCs on a thin endometrium.”
Human uterine stem/progenitor cells: their possible role in uterine physiology and pathology
Maruyama, T., Masuda, H., Ono, M., Kajitani, T., & Yoshimura, Y. (2010) · Reproduction · doi:10.1530/rep-09-0438 · Cited by 122 · see citing works
“Most recent is the fascinating proposal that circulating cells originating from the BM differentiate into endometriotic tissue at various sites (Du & Taylor 2007, Sasson & Taylor 2008).”
BackgroundMolecular Regulation of Parturition: The Role of the Decidual ClockPreprint
Norwitz, E. R., Bonney, E. A., Snegovskikh, V., Williams, M. A., Phillippe, M., Park, J. S., & Abrahams, V. M. (2015) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a023143 · Cited by 120 · see citing works
Peritoneal fluid cytokines related to endometriosis in patients evaluated for infertility
Jørgensen, H., Hill, A. S., Beste, M. T., Kumar, M. P., Chiswick, E. L., Fedorcsák, P., Isaacson, K., Lauffenburger, D. A., Griffith, L. G., & Qvigstad, E. (2017) · Fertility and Sterility · doi:10.1016/j.fertnstert.2017.03.013 · Cited by 120 · see citing works
The Endometrium as a Source of Mesenchymal Stem Cells for Regenerative Medicine1
Mutlu, L., Hufnagel, D. H., & Taylor, H. S. (2015) · Biology of Reproduction · doi:10.1095/biolreprod.114.126771 · Cited by 116 · see citing works
Self-citationCD45-Positive Blood Cells Give Rise to Uterine Epithelial Cells in Mice
Bratincsák, A., Brownstein, M., Cassiani‐Ingoni, R., Pastorino, S., Szalayova, I., Tóth, Z., Key, S., Németh, K., Pickel, J. M., & Mezey, É. (2007) · Stem Cells · doi:10.1634/stemcells.2007-0301 · Cited by 118 · see citing works
Stromal-to-Epithelial Transition during Postpartum Endometrial Regeneration
Huang, C.-C., Orvis, G. D., Wang, Y., & Behringer, R. R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044285 · Cited by 117 · see citing works
“Interestingly, two reports provide evidence that hematopoietic progenitor cells can colonize and differentiate into endometrial epithelium and stroma [26,27].”
BackgroundPatterson, A. L., Zhang, L., Arango, N. A., Teixeira, J. M., & Pru, J. K. (2012) · Stem Cells and Development · doi:10.1089/scd.2012.0435 · Cited by 119 · see citing works
“Recently, it has been proposed that bone marrow-derived cells contribute to uterine regeneration [7–9]; however, the functional contribution of these cells to the endometrium has not yet been established.”
Wang, J., Ju, B., Pan, C., Gu, Y., Zhang, Y., Sun, L. J., Zhang, B., & Zhang, Y. (2016) · Cellular Physiology and Biochemistry · doi:10.1159/000447857 · Cited by 114 · see citing works
Kulak, J., Fischer, C., Komm, B., & Taylor, H. S. (2011) · Endocrinology · doi:10.1210/en.2010-1010 · Cited by 112 · see citing works
“an alternative theory for the etiology of endometriosis (3).”
BackgroundSelf-citationMechanisms of Regeneration and Fibrosis in the Endometrium
Ang, C. J., Skokan, T. D., & McKinley, K. L. (2023) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-011723-021442 · Cited by 121 · see citing works
Endometrial Stem Cell Markers: Current Concepts and Unresolved Questions
Tempest, N., Maclean, A., & Hapangama, D. K. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103240 · Cited by 108 · see citing works
“0003% of CD45-/F4/80- stromal cells of the endometrium [74].”
BackgroundPathogenesis of Benign Metastasizing Leiomyoma
Awonuga, A. O., Shavell, V. I., Imudia, A. N., Rotas, M., Diamond, M. P., & Puscheck, E. E. (2010) · Obstetrical & Gynecological Survey · doi:10.1097/ogx.0b013e3181d60f93 · Cited by 109 · see citing works
“Another possibility is the development BML from circulating stem cells, such as demonstrated by the repopulation of the endometrium in the uterus of female mice and in ectopic endometrium implanted in the peritoneal cavity with male donor-derived bone marrow cells (51).”
BackgroundAsherman’s Syndrome: it may not be all our fault
Santamaría, X., Isaacson, K., & Simón, C. (2018) · Human Reproduction · doi:10.1093/humrep/dey232 · Cited by 107 · see citing works
Stem cell theory for the pathogenesis of endometriosis
Maruyama, T. (2012) · Frontiers in Bioscience · doi:10.2741/e589 · Cited by 109 · see citing works
“Indeed, bone-marrow-derived cells also populate established endometriotic implants in mice (49, 69) and may be found in endometriosis lesions of hysterectomized mice (49).”
BackgroundThe Mesenchymal Stem Cell Antigen MSCA-1 is Identical to Tissue Non-specific Alkaline Phosphatase
Sobiesiak, M., Sivasubramaniyan, K., Hermann, C., Tan, C., Örgel, M., Treml, S., Cerabona, F., de Zwart, P., Ochs, U., Müller, C. A., et al. (2009) · Stem Cells and Development · doi:10.1089/scd.2009.0290 · Cited by 106 · see citing works
“Another possibility is that these cells are derived from bone marrow MSC migrating into endometrial tissue during every menstrual cycle [40,41].”
Cell-based therapy in thin endometrium and Asherman syndrome
Gharibeh, N., Maleki, L. A., Madani, J., Pourakbari, R., Yousefi, M., & Heris, J. A. (2022) · Stem Cell Research & Therapy · doi:10.1186/s13287-021-02698-8 · Cited by 101 · see citing works
“Since BMDSCs exist in both murine and human endometrium, it could be inferred that they have the potential for serving as a reparative cell source for the reproductive tract [91].”
BackgroundChan, R. W. S., Ng, E. H. Y., & Yeung, W. S. B. (2011) · The American Journal of Pathology · doi:10.1016/j.ajpath.2011.02.025 · Cited by 98 · see citing works
“In mice, bone-marrow–derived cells from male donors are involved in endometrial gland formation of female transplant recipients(52) and in ectopic endometrial implants within the peritoneal cavity.(37) Endometrial stromal cells isolated by the expression of perivascular markers [melanoma cell adhesion molecule (MCAM,…”
BackgroundSong, T., Zhao, X., Sun, H., Li, X., Lin, N., Ding, L., Dai, J., & Hu, Y. (2014) · Tissue Engineering Part A · doi:10.1089/ten.tea.2014.0052 · Cited by 101 · see citing works
Cervelló, I., Gil-Sanchis, C., Mas, A., Faus, A., Sanz, J., Moscardó, F., Higueras, G., Sanz, M. A., Pellicer, A., & Simón, C. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030260 · Cited by 99 · see citing works
“Similar endometrial engraftment has been demonstrated In two murine models, Du and Taylor demonstrated the de novo development of the endometrium after injury due to BM stem cells, suggesting an implication between endometriosis and immune disorders [38].”
Rossignoli, F., Caselli, A., Grisendi, G., Piccinno, M. S., Burns, J. S., Murgia, A., Veronesi, E., Loschi, P., Masini, C., Conte, P., et al. (2013) · BioMed Research International · doi:10.1155/2013/901821 · Cited by 97 · see citing works
“In culture, they show mesenchymal morphology and, although some studies suggest they could derive from bone marrow [23], EDT-MSCs are generally considered to originate from the shedding of endometrial stem/progenitor cells which are mainly resident both in the basalis layer and, partially, in the functionalis area of…”
BackgroundThe gut microbiota: a puppet master in the pathogenesis of endometriosis?
Laschke, M. W., & Menger, M. D. (2016) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2016.02.036 · Cited by 95 · see citing works
Cancer-associated mutations in endometriosis: shedding light on the pathogenesis and pathophysiology
Guo, S.-W. (2020) · Human Reproduction Update · doi:10.1093/humupd/dmz047 · Cited by 96 · see citing works
Kong, Y., Shao, Y. W., Ren, C., & Yang, G. S. (2021) · Stem Cell Research & Therapy · doi:10.1186/s13287-021-02526-z · Cited by 94 · see citing works
Transcriptional profiling of endometriosis tissues identifies genes related to organogenesis defects
Crispi, S., Piccolo, M. T., D’Avino, A., Donizetti, A., Viceconte, R., Spyrou, M., Calogero, R., Baldi, A., & Signorile, P. G. (2013) · Journal of Cellular Physiology · doi:10.1002/jcp.24358 · Cited by 92 · see citing works
“The endometrial stem cell theory proposes that the pathology is generated by endometrial stem/progenitor cells naturally located in the endometrium or by circulating stem cells deriving from bone marrow (Chan et al., 2004; Du and Taylor, 2007).”
BackgroundWang, X., Mamillapalli, R., Mutlu, L., Du, H., & Taylor, H. S. (2015) · Stem Cell Research · doi:10.1016/j.scr.2015.04.004 · Cited by 93 · see citing works
“Previous studies from our laboratory showed that BM-derived stem cells can engraft in the murine endometrium (Du and Taylor, 2007).”
BackgroundInfluentialSakr, S., Naqvi, H., Komm, B., & Taylor, H. S. (2014) · Endocrinology · doi:10.1210/en.2013-1977 · Cited by 91 · see citing works
Self-citationMáté, G., Bernstein, L. R., & Török, Á. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00725 · Cited by 93 · see citing works
“The notion has also been advanced that non-endometrial stem cells, such as blood-borne bone marrow derived cells, may also reach the abdominal cavity, differentiate into endometrial cells, and implant in the peritoneum and the surfaces of organs in the abdominal cavity (20).”
BackgroundStem Cell Trafficking During Endometriosis: May Epigenetics Play a Pivotal Role?
Laganà, A. S., Salmeri, F. M., Vitale, S. G., Triolo, O., & Götte, M. (2017) · Reproductive Sciences · doi:10.1177/1933719116687661 · Cited by 86 · see citing works
CD34+KLF4+ Stromal Stem Cells Contribute to Endometrial Regeneration and Repair
Yin, M., Zhou, H. J., Lin, C., Long, L., Yang, X., Zhang, H., Taylor, H. S., & Wang, M. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.04.088 · Cited by 84 · see citing works
“It has been proposed that endometrial stem cells are both fetal epithelial and MSCs remaining in the adult endometrium that continue replicating in adulthood, as well as being derived from circulating stem cells arising from a bone marrow niche that seeds the endometrium periodically or in response to injury (Du and T…”
BackgroundSelf-citationNew Insights in Pathogenesis of Endometriosis
Signorile, P. G., Viceconte, R., & Baldi, A. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.879015 · Cited by 88 · see citing works
“There are several experimental evidences supporting this theory (35, 36).”
BackgroundExpression Pattern of Stemness-Related Genes in Human Endometrial and Endometriotic Tissues
Forte, A., Schettino, M. T., Finicelli, M., Cipollaro, M., Colacurci, N., Cobellis, L., & Galderisi, U. (2009) · Molecular Medicine · doi:10.2119/molmed.2009.00068 · Cited by 86 · see citing works
- Authors
- Du, H., & Taylor, H. S.
- Affiliations
- Yale University (US)
- Corresponding author
- Taylor, Hugh S.
- Venue
- Stem Cells
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-04-26
- Volume
- 25
- Issue
- 8
- Pages
- 2082-2086
- ISSN
- 1066-5099 (ISSN-L)
- 1549-4918
- OpenAlex
- W1986118680
- Cited by
- 449
- References
- 27
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 11 · 2023: 27 · 2022: 28 · 2021: 28 · 2020: 33 · 2019: 30 · 2018: 29 · 2017: 32 · 2016: 17 · 2015: 28 · 2014: 37 · 2013: 23 · 2012: 24
- FWCI
- 8.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Stem Cells (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- bone marrow-derived stem cells, endometrium, endometriosis, bone marrow transplantation, mesenchymal stem cells, endometrial regeneration, stem cell engraftment, sexual dimorphism
- MeSH terms
- Animals, Bone Marrow Cells, Cell Movement, Choristoma, Endometriosis, Endometrium, Female, Keratins, Lac Operon, Male, Mice, Inbred C57BL, Mice, Transgenic, Bone Marrow Transplantation, Mice
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