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Uterine stem cells—promise and possibilities
G Model MAT-6453; No. of Pages 2
ARTICLE IN PRESS Maturitas xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review article
Uterine stem cells—promise and possibilities Lubna Pal Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, CT, USA
a r t i c l e
i n f o
Article history: Received 21 July 2015 Accepted 22 July 2015 Available online xxx Keywords: Stem cell Uterine stem cell Uterus Endometrium
a b s t r a c t A fraction of cells residing in the uterine endometrium exhibit functional pluripotent potential, allowing them to be classified as adult stem cells. While the physiological relevance of this cell population is mostly conjectural at this juncture, uterine endometrial stem cells (UESC’s) may underline pathogenesis of certain common gynecological disorders, such as endometriosis and adenomyosis. The ease of access and harvesting of UESC’s and the diverse differentiation potential of this cell population has identified the uterine endometrium as a valuable source of autologous stem cells that can be harnessed through judicious application of principals of regenerative medicine. This mini review offers a glimpse into the journey, and an introduction to the spectrum of disorders that UESC’s have the potential of impacting. © 2015 Elsevier Ireland Ltd. All rights reserved.
Contents Contributor and role . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Ethical Approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Reference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
A widening appreciation of the diverse array of sources of pluripotent cells, increasing ease of access to and harvesting of these cell populations, and a realization of the need to redefine ethical concepts relating to research on and clinical utilities of stem cells have all contributed to the blossoming in the field of regenerative medicine over the past two decades. Much of the ethical concerns and controversy around potential for misuse has centered on the totipotent embryonic stem cell (ESS) [1]. Focus the adult stem cell (ASC) [2] population, rare undifferentiated pluripotent cells that are present in most adult tissues seems almost an afterthought, primarily driven by roadblocks hurled in the path of embryonic stem cell related research. Similar to the ESC’s, ASC’s hold the potential of differentiation into one or more lineages, and properties of self-renewal and high proliferative potential [2,3]. Bone marrow is recognized as the primary source of origin of ASC’s [4]. Hypoxia, trauma, inflammation and healing processes are recognized systemic stimuli for mobilization and hematogeneous dissemination of bone marrow derived stem cells (BMDSC) number of tissue specific “honing signals” have been identified that attract the circulating BMDSC’s into the tissue [5,6]. While their relevance in tissue physiology currently is more conjectural than substantive, ASC’s are deemed relevant in maintaining tissue homeostasis though provision of replacement cells in routine cellular turnover and for repairing injured tissues [7].
Uterine endometrium and myometrium are amongst the many tissues and organs that have been shown to harbor ASC’s [8–10]. Uterine endometrial stem cells (UESC’s) are described both in the glandular and stromal components of the endometrium; a heterogeneous population, UESC’s are deemed of bone marrow origin [11]. The roles of EMSC’s of diverse lineage in health and in disease are being systematically explored. Interestingly, the processes that underlie menstruation, i.e. endometrial ischemia, tissue breakdown, release of inflammatory cytokines and chemokines, are all recognized stimuli for hematogenous mobilization of BMDSC’s [6]. For now, what is understood is that the endothelial progenitor fraction of EMSC’s may contribute to the cyclic endometrial regeneration of reproductive years [12], and may even be of pathophysiologic relevance for certain common gynecological disorders. Indeed, stem cells contribution to murine endometriosis is well described [13]; localization of BMDSC’s to foci of endometriosis and induction of focal lesions with ectopic stem cell differentiation suggest a “cause and effect” relationship and may explain the occurrence of endometriosis outside of the peritoneal cavity. Similarly, uterine myometrial stem cell population has been implicated in the pathogenesis of uterine fibroids [14]. Given the ease of access to the endometrium, and success with harvesting of the EMSC’s, increasing attention has focused on
http://dx.doi.org/10.1016/j.maturitas.2015.07.018 0378-5122/© 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: L. http://dx.doi.org/10.1016/j.maturitas.2015.07.018
Pal,
Uterine
stem
cells—promise
and
possibilities,
Maturitas
(2015),
G Model MAT-6453; No. of Pages 2
ARTICLE IN PRESS L. Pal / Maturitas xxx (2015) xxx–xxx
2
potential for harnessing and channelizing the pluripotent capabilities of this population. Beyond the in vitro successes in achieving in vitro differentiation of UESC’s into neurogenic, myogenic, chondrogenic and osteogenic cells, genesis of functioning dopamine secreting neurons and insulin secreting beta cells (in rodents), evidence of myocardial salvage with uterine stem cells following ischemic injury in mice, restoration of normal endometrium in animal models of Asherman syndrome has launched this cell population as forerunners spearheading advances in regenerative medicine [12,15–22]. In summary, while a physiological relevance of UESC’s may not be obvious at present, their potential for therapeutic benefit inherent to ease of accessibility, sustained replenishment and pluripotency is profound. It is furthermore plausible that the monthly mobilization of bone marrow derived pluripotent cells, under directives of the endometrial milieu of reproductive years, be a steady source tissue repair, replenishment and rejuvenation, thus explaining the many health advantages (cardiovascular being on top of the list) apparent in reproductive age women to age comparable males [23]. Given that UESC’s have been isolated from postmenopausal uteri, postmenopausal hysterectomies can no longer be trivialized; the uterine endometrium, as a source of autologous stem cells, may indeed hold the promise of assuring quality longevity through emerging applications of regenerative medicine. Contributor and role Submitting author is the sole contributor responsible in entirety for this mini-review. Ethical Approval Not applicable. Funding None. References [1] I. Hyun, The bioethics of stem cell research and therapy, J. Clin. Invest. 120 (1) (2010) 71–75. [2] A. Wabik, P.H. Jones, Switching roles: the functional plasticity of adult tissue stem cells, EMBO J. 34 (9) (2015) 1164–1179.
Please cite this article in press as: L. http://dx.doi.org/10.1016/j.maturitas.2015.07.018
Pal,
Uterine
[3] C.E. Eckfeldt, E.M. Mendenhall, C.M. Verfaillie, The molecular repertoire of the ‘almighty’ stem cell, Nat. Rev. Mol. Cell. Biol. 6 (2005) 726–737. [4] M.Z. Ratajczak, A novel view of the adult bone marrow stem cell hierarchy and stem cell trafficking, Leukemia 29 (4) (2015) 776–782. [5] B.D. Simons, H. Clevers, Strategies for homeostatic stem cell self-renewal in adult tissues, Cell 145 (6) (2011) 851–862. [6] J. Hoggatt, L.M. Pelus, Mobilization of hematopoietic stem cells from the bone marrow niche to the blood compartment, Stem Cell Res. The.r 14 (2(2)) (2011) 13. [7] L. Li, T. Xie, Stem cell niche: structure and function, Annu. Rev. Dev. Biol. Rev. Cell 21 (2005) 605–631. [8] J. Teixeira, B.R. Rueda, J.K. Pru, Uterine Stem cells (September 30, 2008), StemBook, ed. The Stem Cell Research Community, StemBook, doi/10.3824/stembook.1.16.1, http://www.stembook.org [9] C.E. Gargett, H. Masuda, Adult stem cells in the endometrium, Mol. Hum. Reprod. 16 (11) (2010) 818–834. [10] X. Meng, T.E. Ichim, J. Zhong, A. Rogers, Z. Yin, J. Jackson, H. Wang, W. Ge, V. Bogin, K.W. Chan, B. Thébaud, N.H. Riordan, Endometrial regenerative cells: a novel stem cell population, J. Transl. Med. 5 (2007) 57. [11] H.S. Taylor, Endometrial cells derived from donor stem cells in bone marrow transplant recipients, JAMA 292 (1) (2004) 81–85. [12] C.E. Gargett, L. Ye, Endometrial reconstruction from stem cells, Fertil. Steril. 98 (2012) 11–20. [13] H. Du, H.S. Taylor, Contribution of bone marrow-derived stem cells to endometrium and endometriosis, Stem Cells 25 (8) (2007) 2082–2086. [14] M.B. Moravek, P. Yin, M. Ono, J.S. Coon 5, D. th, M.T. yson, A. Navarro, E.E. Marsh, D. Chakravarti, J.J. Kim, J.J. Wei, S.E. Bulun, Ovarian steroids, stem cells and uterine leiomyoma: therapeutic implications, Hum. Reprod. Update. 21 (1 January) (2015) 1–12. [15] H. Du, H.S. Taylor, Stem cells and reproduction, Curr. Opin. Obstet. Gynecol. 22 (3) (2010) 235–241. [16] E.F. Wolff, A.B. Wolff, Du Hongling, H.S. Taylor, Demonstration of multipotent stem cells in the adult human endometrium by in vitro chondrogenesis, Reprod. Sci. 14 (6) (2007) 524–533. [17] E.F. Wolff, X.B. Gao, K.V. Yao, et al., Endometrial stem cell transplantation restores dopamine production in a Parkinson’s disease model, J. Cell Mol Med. 15 (4) (2011) 747–755. [18] X. Santamaria, E.E. Massasa, Y. Feng, E. Wolff, H.S. Taylor, Derivation of insulin producing cells from human endometrial stromal stem cells and use in the treatment of murine diabetes, Mol. Ther. 19 (11) (2011) 2065–2071. [19] Z. iang, X. Hu, H. Yu, Y. Xu, L. Wang, H. Chen, H. Chen, R. Wu, Z. Zhang, C. Xiang, K.A. Webster, J.A. Wang, Human endometrial stem cells confer enhanced myocardial salvage and regeneration by paracrine mechanisms, J. Cell. Mol. Med. 17 (2013) 1247–1260. [20] A. Ludke, J. Wu, M. Nazari, K. Hatta, Z. Shao, S.H. Li, H. Song, N.C. Ni, R.D. Weisel, R.K. Li, Uterine-derived progenitor cells are immunoprivileged and effectively improve cardiac regeneration when used for cell therapy, J. Mol. Cell. Cardiol. 84 (2015) 116–128. [21] L. Bockeria, V. Bogin, O. Bockeria, T. Le, B. Alekyan, E.J. Woods, A.A. Brown, T.E. Ichim, A.N. Patel, Endometrial regenerative cells for treatment of heart failure: a new stem cell enters the clinic, J. Transl. Med. 11 (2013) 56. [22] D. Ulrich, K.S. Tan, J. Deane, K. Schwab, A. Cheong, A. Rosamilia, C.E. Gargett, Mesenchymal stem/stromal cells in post-menopausal endometrium, Hum. Reprod. 29 (2014) 1895–1905. [23] V. Regitz-Zagrosek, U. Seeland, Sex and gender differences in clinical medicine, Handb. Exp. Pharmacol. 214 (2012) 3–22.
stem
cells—promise
and
possibilities,
Maturitas
(2015),
ARTICLE IN PRESS Maturitas xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review article
Uterine stem cells—promise and possibilities Lubna Pal Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, CT, USA
a r t i c l e
i n f o
Article history: Received 21 July 2015 Accepted 22 July 2015 Available online xxx Keywords: Stem cell Uterine stem cell Uterus Endometrium
a b s t r a c t A fraction of cells residing in the uterine endometrium exhibit functional pluripotent potential, allowing them to be classified as adult stem cells. While the physiological relevance of this cell population is mostly conjectural at this juncture, uterine endometrial stem cells (UESC’s) may underline pathogenesis of certain common gynecological disorders, such as endometriosis and adenomyosis. The ease of access and harvesting of UESC’s and the diverse differentiation potential of this cell population has identified the uterine endometrium as a valuable source of autologous stem cells that can be harnessed through judicious application of principals of regenerative medicine. This mini review offers a glimpse into the journey, and an introduction to the spectrum of disorders that UESC’s have the potential of impacting. © 2015 Elsevier Ireland Ltd. All rights reserved.
Contents Contributor and role . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Ethical Approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Reference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
A widening appreciation of the diverse array of sources of pluripotent cells, increasing ease of access to and harvesting of these cell populations, and a realization of the need to redefine ethical concepts relating to research on and clinical utilities of stem cells have all contributed to the blossoming in the field of regenerative medicine over the past two decades. Much of the ethical concerns and controversy around potential for misuse has centered on the totipotent embryonic stem cell (ESS) [1]. Focus the adult stem cell (ASC) [2] population, rare undifferentiated pluripotent cells that are present in most adult tissues seems almost an afterthought, primarily driven by roadblocks hurled in the path of embryonic stem cell related research. Similar to the ESC’s, ASC’s hold the potential of differentiation into one or more lineages, and properties of self-renewal and high proliferative potential [2,3]. Bone marrow is recognized as the primary source of origin of ASC’s [4]. Hypoxia, trauma, inflammation and healing processes are recognized systemic stimuli for mobilization and hematogeneous dissemination of bone marrow derived stem cells (BMDSC) number of tissue specific “honing signals” have been identified that attract the circulating BMDSC’s into the tissue [5,6]. While their relevance in tissue physiology currently is more conjectural than substantive, ASC’s are deemed relevant in maintaining tissue homeostasis though provision of replacement cells in routine cellular turnover and for repairing injured tissues [7].
Uterine endometrium and myometrium are amongst the many tissues and organs that have been shown to harbor ASC’s [8–10]. Uterine endometrial stem cells (UESC’s) are described both in the glandular and stromal components of the endometrium; a heterogeneous population, UESC’s are deemed of bone marrow origin [11]. The roles of EMSC’s of diverse lineage in health and in disease are being systematically explored. Interestingly, the processes that underlie menstruation, i.e. endometrial ischemia, tissue breakdown, release of inflammatory cytokines and chemokines, are all recognized stimuli for hematogenous mobilization of BMDSC’s [6]. For now, what is understood is that the endothelial progenitor fraction of EMSC’s may contribute to the cyclic endometrial regeneration of reproductive years [12], and may even be of pathophysiologic relevance for certain common gynecological disorders. Indeed, stem cells contribution to murine endometriosis is well described [13]; localization of BMDSC’s to foci of endometriosis and induction of focal lesions with ectopic stem cell differentiation suggest a “cause and effect” relationship and may explain the occurrence of endometriosis outside of the peritoneal cavity. Similarly, uterine myometrial stem cell population has been implicated in the pathogenesis of uterine fibroids [14]. Given the ease of access to the endometrium, and success with harvesting of the EMSC’s, increasing attention has focused on
http://dx.doi.org/10.1016/j.maturitas.2015.07.018 0378-5122/© 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: L. http://dx.doi.org/10.1016/j.maturitas.2015.07.018
Pal,
Uterine
stem
cells—promise
and
possibilities,
Maturitas
(2015),
G Model MAT-6453; No. of Pages 2
ARTICLE IN PRESS L. Pal / Maturitas xxx (2015) xxx–xxx
2
potential for harnessing and channelizing the pluripotent capabilities of this population. Beyond the in vitro successes in achieving in vitro differentiation of UESC’s into neurogenic, myogenic, chondrogenic and osteogenic cells, genesis of functioning dopamine secreting neurons and insulin secreting beta cells (in rodents), evidence of myocardial salvage with uterine stem cells following ischemic injury in mice, restoration of normal endometrium in animal models of Asherman syndrome has launched this cell population as forerunners spearheading advances in regenerative medicine [12,15–22]. In summary, while a physiological relevance of UESC’s may not be obvious at present, their potential for therapeutic benefit inherent to ease of accessibility, sustained replenishment and pluripotency is profound. It is furthermore plausible that the monthly mobilization of bone marrow derived pluripotent cells, under directives of the endometrial milieu of reproductive years, be a steady source tissue repair, replenishment and rejuvenation, thus explaining the many health advantages (cardiovascular being on top of the list) apparent in reproductive age women to age comparable males [23]. Given that UESC’s have been isolated from postmenopausal uteri, postmenopausal hysterectomies can no longer be trivialized; the uterine endometrium, as a source of autologous stem cells, may indeed hold the promise of assuring quality longevity through emerging applications of regenerative medicine. Contributor and role Submitting author is the sole contributor responsible in entirety for this mini-review. Ethical Approval Not applicable. Funding None. References [1] I. Hyun, The bioethics of stem cell research and therapy, J. Clin. Invest. 120 (1) (2010) 71–75. [2] A. Wabik, P.H. Jones, Switching roles: the functional plasticity of adult tissue stem cells, EMBO J. 34 (9) (2015) 1164–1179.
Please cite this article in press as: L. http://dx.doi.org/10.1016/j.maturitas.2015.07.018
Pal,
Uterine
[3] C.E. Eckfeldt, E.M. Mendenhall, C.M. Verfaillie, The molecular repertoire of the ‘almighty’ stem cell, Nat. Rev. Mol. Cell. Biol. 6 (2005) 726–737. [4] M.Z. Ratajczak, A novel view of the adult bone marrow stem cell hierarchy and stem cell trafficking, Leukemia 29 (4) (2015) 776–782. [5] B.D. Simons, H. Clevers, Strategies for homeostatic stem cell self-renewal in adult tissues, Cell 145 (6) (2011) 851–862. [6] J. Hoggatt, L.M. Pelus, Mobilization of hematopoietic stem cells from the bone marrow niche to the blood compartment, Stem Cell Res. The.r 14 (2(2)) (2011) 13. [7] L. Li, T. Xie, Stem cell niche: structure and function, Annu. Rev. Dev. Biol. Rev. Cell 21 (2005) 605–631. [8] J. Teixeira, B.R. Rueda, J.K. Pru, Uterine Stem cells (September 30, 2008), StemBook, ed. The Stem Cell Research Community, StemBook, doi/10.3824/stembook.1.16.1, http://www.stembook.org [9] C.E. Gargett, H. Masuda, Adult stem cells in the endometrium, Mol. Hum. Reprod. 16 (11) (2010) 818–834. [10] X. Meng, T.E. Ichim, J. Zhong, A. Rogers, Z. Yin, J. Jackson, H. Wang, W. Ge, V. Bogin, K.W. Chan, B. Thébaud, N.H. Riordan, Endometrial regenerative cells: a novel stem cell population, J. Transl. Med. 5 (2007) 57. [11] H.S. Taylor, Endometrial cells derived from donor stem cells in bone marrow transplant recipients, JAMA 292 (1) (2004) 81–85. [12] C.E. Gargett, L. Ye, Endometrial reconstruction from stem cells, Fertil. Steril. 98 (2012) 11–20. [13] H. Du, H.S. Taylor, Contribution of bone marrow-derived stem cells to endometrium and endometriosis, Stem Cells 25 (8) (2007) 2082–2086. [14] M.B. Moravek, P. Yin, M. Ono, J.S. Coon 5, D. th, M.T. yson, A. Navarro, E.E. Marsh, D. Chakravarti, J.J. Kim, J.J. Wei, S.E. Bulun, Ovarian steroids, stem cells and uterine leiomyoma: therapeutic implications, Hum. Reprod. Update. 21 (1 January) (2015) 1–12. [15] H. Du, H.S. Taylor, Stem cells and reproduction, Curr. Opin. Obstet. Gynecol. 22 (3) (2010) 235–241. [16] E.F. Wolff, A.B. Wolff, Du Hongling, H.S. Taylor, Demonstration of multipotent stem cells in the adult human endometrium by in vitro chondrogenesis, Reprod. Sci. 14 (6) (2007) 524–533. [17] E.F. Wolff, X.B. Gao, K.V. Yao, et al., Endometrial stem cell transplantation restores dopamine production in a Parkinson’s disease model, J. Cell Mol Med. 15 (4) (2011) 747–755. [18] X. Santamaria, E.E. Massasa, Y. Feng, E. Wolff, H.S. Taylor, Derivation of insulin producing cells from human endometrial stromal stem cells and use in the treatment of murine diabetes, Mol. Ther. 19 (11) (2011) 2065–2071. [19] Z. iang, X. Hu, H. Yu, Y. Xu, L. Wang, H. Chen, H. Chen, R. Wu, Z. Zhang, C. Xiang, K.A. Webster, J.A. Wang, Human endometrial stem cells confer enhanced myocardial salvage and regeneration by paracrine mechanisms, J. Cell. Mol. Med. 17 (2013) 1247–1260. [20] A. Ludke, J. Wu, M. Nazari, K. Hatta, Z. Shao, S.H. Li, H. Song, N.C. Ni, R.D. Weisel, R.K. Li, Uterine-derived progenitor cells are immunoprivileged and effectively improve cardiac regeneration when used for cell therapy, J. Mol. Cell. Cardiol. 84 (2015) 116–128. [21] L. Bockeria, V. Bogin, O. Bockeria, T. Le, B. Alekyan, E.J. Woods, A.A. Brown, T.E. Ichim, A.N. Patel, Endometrial regenerative cells for treatment of heart failure: a new stem cell enters the clinic, J. Transl. Med. 11 (2013) 56. [22] D. Ulrich, K.S. Tan, J. Deane, K. Schwab, A. Cheong, A. Rosamilia, C.E. Gargett, Mesenchymal stem/stromal cells in post-menopausal endometrium, Hum. Reprod. 29 (2014) 1895–1905. [23] V. Regitz-Zagrosek, U. Seeland, Sex and gender differences in clinical medicine, Handb. Exp. Pharmacol. 214 (2012) 3–22.
stem
cells—promise
and
possibilities,
Maturitas
(2015),