Using stem cells as a new approach for treatment of polycystic ovary syndrome

Subject Areas : Developmental biology of plants and animals , development and differentiation in microorganisms

somayeh ebrahimi-barough ¹ , fatemeh kouchakzadeh ² , seyyed mahdi kalantar ³ , jafar Ai ⁴ , behrooz aflatoonian ⁵

1 - tehran university of medical sciences
2 - tehran university of medical sciences
3 - shahid sadoghi medical university
4 - tehran university of medical sciences
5 - shahid sadogi medical university

Received: 2023-01-18 Accepted : 2023-03-10 Published : 2023-11-22

Keywords: Treatment, stem cells, Polycystic ovary syndrome, regenerative medicine,

Abstract :

Polycystic ovary syndrome (PCOS) is a common disorder in women that usually occurs in reproductive age in a number of people around the world. Symptoms include impaired folliculogenesis, hyperandrogenism, menstrual irregularities, numerous small cystic follicles, infertility, and chronic anovulation. The present review study was conducted with the aim of describing the use of stem cells for the treatment of PCOS, their biological characteristics and mechanism of action. The information related to this review study was collected from 53 papers that searched from databases such as SID, Magiran, PubMed, Google Scholar, Ironed Scopus and clinicaltrials. Currently, only the studies are at the level of pre-clinical studies on bone marrow mesenchymal stem cells, adipose stem cells, cord blood stem cells and exosomes derived mesenchymal stem cells, and there are only two studies on the Clinicaltrials.gov website as clinical studies. Due to the uncertainty of the safety of this method for the purpose of using stem cells in human, more studies in this field should be designed and implemented.

References:

[1] Vezza T, Rocha M, Víctor VM.
EBioMedicine. PGK1-AR axis: Benefits
of a novel actor in PCOS pathology.
EBioMedicine. 2020;62:103110.
[2] Li X, Feng Y, Lin JF, Billig H, Shao R. J
Biomed Sci. Endometrial progesterone
resistance and PCOS. EBioMedicine.
2014; 21(1):2.
[3] Rosenfield RL. Curr Opin Pediatr. Current
concepts of polycystic ovary syndrome
pathogenesis. Curr Opin Pediatr
2020;32(5):698-706.
[4] Khan MJ, Ullah A, Basit S. Appl Clin
Genet. Genetic Basis of Polycystic Ovary
Syndrome (PCOS): Current Perspectives.
Appl Clin Genet. 2019;12:249-260.
[5] Yuanyuan Li, Jia Guo, Shoulong Deng ,
Zili Gao, Yixun Liu and Qi Gu, Appl.
Sci. Fibrin Facilitates Mesenchymal Stem
Cells to Ameliorate Rats with Polycystic
Ovary Syndrome Appli Sci. 2020; 10(10):
3598.
[6] Maas K, Mirabal S, Penzias A, Sweetnam
PM, Eggan KC, Sakkas D. J. Hippo
signaling in the ovary and polycystic

ovarian syndrome. Assist Reprod Genet.
2018;35(10):1763-1771.
[7] Diamanti-Kandarakis EDA. Insulin
resistance and the polycystic ovary
syndrome revisited: an update on
mechanisms and implications. Endocrinol.
2012;33:981–1030
[8] Woods DC,Tilly JL. Autologousgermline
mitochondrial energy transfer
(AUGMENT) in Human assisted
reproduction. Semin. Reprod. Med.
2015;33(6):410–421.
[9] White YA., Woods DC, Takai Y, Ishihara
O, Seki H, Tilly JL. Oocyte formation by
mitotically active germ cells purified from
ovaries of reproductive-age women. Nat.
Med. 2012;18(3):413–421.
[10] Li J, Mao Q, He J, She H, Zhang Z, Yin
C. Human umbilical cord mesenchymal
stem cells improve the reserve function of
perimenopausal ovary via a paracrine
mechanism. Stem Cell Res. Ther.
2017;8(1):55.
[11]

فصلنامه علمی زیست شناسی تکوینی سال پانزدهم، شماره 4، پاییز 1402 9
[12] Mohamed SA, Shalaby SM, Abdelaziz M.
Human mesenchymal stem cells partially
reverse infertility in chemotherapy-
induced ovarian failure. Reprod Sci.
2018;25(1):51–63.
[13] Liu T, Huang Y, Zhang J. Transplantation
of human menstrual blood stem cells to
treat premature ovarian failure in mouse
model. Stem Cells
Dev.2014;23(13):1548–1557.
[14] Xiao GY, Cheng CC, Chiang YS, Cheng
WT, Liu IH, Wu SC. Exosomal miR-10a
derived from amniotic fluid stem cells
preserves ovarian follicles after
chemotherapy. Sci Rep. 2016;6:23120.
[15] Yun-Xing F, Jing J, Fang S, Jialing L and
Rong H, Fu.Human mesenchymal stem
cell treatment of premature ovarian
failure: new challenges and opportunities.
Stem Cel Res Ther. 2021; 3;12(1):161.
[16] Akiyama K, You YO, Yamaza T, Chen C,
Tang L, Jin Y, Chen XD, Gronthos S, Shi
S. Characterization of bone marrow
derived mesenchymal stem cells in
suspension. Stem Cell Res Ther. 2012 ;
3(5):40. 
[17] Han Y, Li X, Zhang Y, Han Y, Chang F,
Ding J. Mesenchymal Stem Cells for
Regenerative Medicine. Cells 2019, 8:
886.
[18] Zhang J, Huang X, Wang H, Liu X,
Zhang T, Wang Y, Hu D. The challenges
and promises of allogeneic mesenchymal
stem cells for use as a cell-based therapy.
Stem Cell Res Ther. 2015; 6: 234.
[19] Fan, X.-L, Zhang Y, Li X, Fu Q-L.
Mechanisms underlying the protective
effects of mesenchymalstem cell-based
therapy. Cell Mol Life Sci. 2020; 77:
2771–2794
[20] Harrell CR., Fellabaum C, Jovicic N,
Djonov V, Arsenijevic N, Volarevic V.
Molecular Mechanisms Responsible for
Therapeutic Potential of Mesenchymal
Stem Cell-Derived Secretome. Cells 2019;
8: 467.
[21] Chapel A, Bertho JM, Bensidhoum M,
Fouillard L, Young RG, Frick J,
Demarquay C, Cuvelier F, Mathieu E,
Trompier F. Mesenchymal stem cells
home to injured tissues when co-infused
with hematopoieticcells to treat a
radiation-induced multi-organ failure

syndrome. J Gene Med. 2003; 5:
1028–1038.
[22] Salgado AJ, Reis RL, Sousa NJ, Gimble
JM. Adipose tissue derived stem cells
secretome: Soluble factors and their roles
in regenerative medicine. Curr Stem Cell
Res Ther. 2010; 5: 103–110.
[23] Xie Q, Xiong X, Xiao N, He K, Chen M,
Peng J, Su X, Mei H, Dai Y, Wei D.
Mesenchymal Stem Cells Alleviate
DHEA-Induced Polycystic Ovary
Syndrome (PCOS) by Inhibiting
Inflammation in Mice. Stem Cells Int.
2019; 9782373.
[24] Marti N, Bouchoucha N, Sauter KS, Flück
CE. Resveratrol inhibits androgen
production of human adrenocortical
H295R cells by lowering CYP17 and
CYP21 expression and activities. PLoS
ONE 2017; 1: e0174224.
[25] Chugh RM, Park HS, Andaloussi A.
Elsharoud A, Esfandyari S, Ulin M, Bakir
L, Aboalsoud A, Ali M, Ashour D.
Mesenchymal stem cell therapy
ameliorates metabolic dysfunction and
restores fertility in a PCOS mouse model
through interleukin-10. Stem Cell Res
Ther. 2021; 12: 388. .
[26] Dilogo I.H, Fiolin J, Aprianto P.
Osteogenic Potency of Secretome Bone
Marrow Derived Mesenchymal Stem
Cells: Adv Sci Lett. 2018; 24:6206–6208.
[27] Yoshino O, Shi J, Osuga Y, Harada M,
Nishii O, Yano T, Taketani Y. The
function of bone morphogenetic proteins
in the human ovary. Reprod Med Biol.
2011; 10:1–7.
[28] Otsuka F, Inagaki K. Unique bioactivities
of bone morphogenetic proteinsin
regulation of reproductive endocrine
functions. Reprod Med Biol. 2011; 10:
131–142.
[29] Houten V, Laven E.L, Louwers JS,
McLuskey YV, Themmen A, Visser AP.
Bone morphogenetic proteins and the
polycystic ovary syndrome. J
Ovarian.Res. 2013; 6: 32.
[30] Bremer, AA. Polycystic Ovary Syndrome
in the Pediatric Population. Metab Syndr
Relat Disord. 2010; 8: 375–394.
[31] Zhang J, Ge Y, Sun L, Cao J, Wu Q, Guo
L, Wang Z. Effect of bone morphogenetic
protein-2 on proliferation and apoptosis of

10 استفاده از سلول‏های بنیادی به عنوان رویکرد جدید برای درمان سندرم تخمدان پلی‏کیستیک / فاطمه کوچک زاده و همکاران
gastric cancer cells. Int J Med Sci. 2012;
9: 184–192.
[32] Glister C, Satchell L, Bathgate RAD,
Wade JD, Dai Y, Ivell R., Anand-Ivell R,
Rodgers RJ, Knight PG. Functional link
between bone morphogenetic proteins and
insulin-like peptide 3 signaling in
modulating ovarian androgen production.
Proc Natl Acad Sci. 2013; 110:
E1426–E1435.
[33] Chugh RM, Park H, Esfandyari S, Amro
Elsharoud , Mara Ulin and Ayman Al-
Hendy, Int.Mesenchymal Stem Cell-
Conditioned Media Regulate
Steroidogenesis and Inhibit Androgen
Secretion in a PCOS Cell Modelvia BMP-
2, J. Mol. Sci. 2021.
[34] F. González, “Inflammation in polycystic
ovary syndrome: underpinning of insulin
resistance and ovarian dysfunction,”
Steroids, vol. 77, no. 4, pp. 300–305,
2012.
[35] Y. Yang, J. Qiao, R. Li, and M. Z. Li, “Is
interleukin-18 associated with polycystic
ovary syndrome?,” Reproductive Biology
and Endocrinology, vol. 9, no. 1, p. 7,
2011.
[36] A. Gallinelli, I. Ciaccio, L. Giannella, M.
Salvatori, T. Marsella, and A. Volpe,
“Correlations between concentrations of
interleukin-12 and interleukin-13 and
lymphocyte subsets in the follicular fluid
of women with and without polycystic
ovary syndrome,” Fertility and Sterility,
vol. 79, no. 6, pp. 1365–1372, 2003.
[37] A. C. Herlihy, R. E. Kelly, J. L. Hogan, N.
O'Connor, N. Farah, and M. J. Turner,
“Polycystic ovary syndrome and the
peripheral blood white cell count,” Journal
of Obstetrics and Gynaecology, vol. 31,
no. 3, pp. 2011.
[38] H. Lu, F. Wang, H. Mei, S. Wang, and L.
Cheng, “Human adipose mesenchymal
stem cells show more efficient
angiogenesis promotion on endothelial
colony-forming cells than umbilical cord
and endometrium,” Stem Cells
International, vol. 2018, Article ID
7537589, 15 pages, 2018.
[39] M. Ajuebor, A. Das, L. Virág, R. J.
Flower, C. Szabó, and M. Perretti, “Role
of resident peritoneal macrophages and
mast cells in chemokine production and
neutrophil migration in acute

inflammation: evidence for an inhibitory
loop involving endogenous IL-10,” The
Journal of Immunology, vol. 162, no. 3,
pp. 1685–1691, 1999.
[40] Dash B C, Xu Z , Lin L , Koo A, Ndon S,
Berthiaume F, Dardik A and Hsia H.
(2018): Stem Cells and Engineered
Scaffolds for Regenerative Wound
Healing Bioengineering,. 5 (23): 1-12.
[41] Li H, Xu Y, Fu Q and Li C. Effects of
multiple agents on epithelial
differentiation of rabbit adipose-derived
stem cells in 3D culture. Tissue Engin.
2012;18(17): 1760–70.
[42] DiMarino A M, Caplan A I, and Bonfield
T L. Mesenchymal Stem Cells in Tissue
Repair Front Immunol.2013; 4: 201.
[43] Tadros J, Dina H, Marwa M S, Hefney
AH. Effect of Adipose-derived stem cells
versus clomiphen on treatment of
experimental polycystic ovary in rats:
Histological and Immunohistochemistry
study. Histol. 2018 ; 41 (4) : 373-385
[44] Liao Z, Liu C, Wang L, Sui C, Zhang H.
Therapeutic Role of Mesenchymal Stem
Cell-Derived Extracellular Vesicles in
Female Reproductive Diseases. Front
Endocrinol (Lausanne). 2021;12:665645.
[45] Cao M, Zhao Y, Chen T, Zhao Z, Zhang
B, Yuan C, Wang X, Chen L, Wang N, Li
C, Zhou X. Adipose mesenchymal stem
cell-derived exosomal microRNAs
ameliorate polycystic ovary syndrome by
protecting against metabolic disturbances.
Biomaterials. 2022. 288:121739
[46] Zhao Y,Tao M, Wei M, Du, Hongping
Wang H, Wang X. Mesenchymal stem
cells derived exosomal miR-323-3p
promotes proliferation and inhibits
apoptosis of cumulus cells in polycystic
ovary syndrome (PCOS). Artif Nanomed
Biotechnol. 2019; 47(1):3804-3813|
[47] Zhang M, Jin K, Gao L, Zhang Z, Li F,
Zhou F, Zhang L. Methods and
technologies for exosome isolation and
characterization. Small Methods. 2018;
2(9): 1800021
[48] Cuiffo BG, Karnoub AE. Mesenchymal
stem cells in tumor development emerging
roles and concepts. Cell Adh Migr.2012;
6(3): 220–230.
[49] Qi X, Xiong X , Xiao N , He K, Chen M,
Peng J , Xian S , Mei H , Dai Y , Wei D ,
Lin G , Cheng L. Mesenchymal Stem

فصلنامه علمی زیست شناسی تکوینی سال پانزدهم، شماره 4، پاییز 1402 11
Cells Alleviate DHEA-Induced Polycystic
Ovary Syndrome (PCOS) by Inhibiting
Inflammation in Mice. Stem cell int. 2019;
9782373.
[50] Liao Z, Liu C, Wang L, Sui C, Zhang H.
Therapeutic Role of Mesenchymal Stem
Cell-Derived Extracellular Vesicles in
Female Reproductive Diseases. Front
Endocrinol (Lausanne). 2021;
23:12:665645.
[51] Budi S, Agus S, Salmon Charles S,
Widjiati, Majalah Obstetri & Ginekologi,
Therapeutic effectiveness of rat bone
marrow stem cells in Poly Cystic Ovary
Syndrome Mice Model on
folliculogenesis, TGF-β, GDF-9
expression, and estrogen, TNF-a and
androgen Levels. Majalah Obstetri &
Ginekologi. 2016; 24(3):90-93
[52]
https://clinicaltrials.gov/ct2/show/NCT052
79768
[53] Chugh R, Ashour D, Garcia G, Takala H,
Ismail N, McAllister J, Al-Hendy A, El
Andaloussi A. Towards cell therapy of
polycystic ovary syndrome (PCOS):
human mesenchymal stem cells secretome
inhibits androgen production by pcos
theca cells. Cytotherapy. 2019; 21(5):s81
[54] Zhao Y, Pan S ,  Wu X. Human umbilical
cord mesenchymal stem cell-derived
exosomes inhibit ovarian granulosa cells
inflammatory response through inhibition
of NF-κB signaling in polycystic ovary
syndrome. J Reproduct Immunol.2011;
152:103638.