Scientific research reveals: 4 potential mechanisms of mesenchymal stem cells in the treatment of premature ovarian failure

In recent years, scientists have been able to use stem cells to intervene in premature ovarian failure, enabling infertile women to regain the ability to reproduce.
Mesenchymal stem cells are the most commonly used stem cell type in clinical treatment research for premature ovarian failure.
In 2018, my country ushered in the first healthy baby born in a clinical trial of stem cell treatment of premature ovarian failure, using mesenchymal stem cells.

So, how do mesenchymal stem cells help repair premature ovarian failure? How to play a role in the treatment of premature ovarian failure? Recently, a document published in Front Endocrinol magazine elaborated on the 4 potential mechanisms of mesenchymal stem cells in the treatment of premature ovarian failure, so that everyone can further understand how mesenchymal stem cells can be transformed into "Send Son Guanyin" and help families with premature ovarian failure realize their dream of giving birth.

Premature ovarian failure: traditional methods are not yet effective

Premature ovarian failure: traditional methods are not yet effective

Premature ovarian failure (POF) refers to women’s ovarian failure due to a variety of causes before the age of 40, which is considered an "incurable disease" that causes infertility.
According to statistics, about 1% of the global female population under the age of 40 suffer from premature ovarian failure.
In recent years, the incidence of premature ovarian failure has been on the rise, which has a certain relationship with the accelerated pace of life and the increase in life pressure.

Picture from literature [1]

Picture from literature [1]

Some of the current traditional measures have no obvious therapeutic effect on premature ovarian failure.
How to "rejuvenate" the ovaries is the greatest hope of patients.
In recent years, the regeneration and immunomodulatory properties of stem cells have been successfully tested in different tissues including the ovary.
A large number of studies have pointed out the effectiveness of stem cells in POF treatment.
The types of stem cells involved include amniotic fluid mesenchymal stem cells, umbilical cord mesenchymal stem cells, bone marrow mesenchymal stem cells, etc.
These stem cells secrete a large number of soluble factors and chemokines through paracrine effects.
, Involved in immune regulation, anti-fibrosis, regulating angiogenesis, etc.
[1].

Picture from literature [1]

Picture from literature [1]

Mechanism 1: Regulate ovarian angiogenesis

Mechanism 1: Regulate ovarian angiogenesis

Studies have found that after an animal model of premature ovarian failure receives mesenchymal stem cell transplantation, angiogenesis in the ovarian niche is increased, which improves the healing process that occurs periodically, which may be beneficial to the recovery of the ovary [2].
Factors produced by stem cells, such as vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF2) and interleukin-6 (IL-6), can promote arteriogenesis in vitro and in vivo [3].
The research results of other research teams also show [4] that mesenchymal stem cells significantly increase the angiogenesis and blood perfusion of the transplanted ovaries.

Picture 1: Picture from literature [4]

Picture 1: Picture from literature [4]

Picture from literature [4]

Picture from literature [4]

Mechanism 2: Promote the survival of primordial follicles and prevent granulosa cell apoptosis

Mechanism 2: Promote the survival of primordial follicles and prevent granulosa cell apoptosis

The number of follicles in the ovaries of patients with premature ovarian failure is significantly reduced.
Studies have found [5] that mesenchymal stem cells can promote the survival of follicles by secreting proteins such as angiopoietin (ANG).
After using ANG antibody to neutralize the angiogenin secreted by mesenchymal stem cells, a significant decrease in the survival rate of follicles can be observed.

Picture from literature [5]

Picture from literature [5]

In addition, mesenchymal stem cells can also reduce the apoptosis of granulosa cells.
It has been reported that [6] co-culture with BMSCs can reduce the levels of pro-apoptotic proteins P21 and Bax in granulosa cells, and increase the levels of proto-oncogene c-myc.
It has been observed that there are different cytokines VEGF, HGF, and HGF in the culture medium of BMSCs.
IG F-1 can reduce the apoptosis of granular cells in vitro and in vivo, and promote their proliferation.

Mechanism three: immune regulation

Mechanism three: immune regulation

Mesenchymal stem cells have a powerful immune regulation function, which corrects immune imbalance by releasing a variety of active substances.
Mesenchymal stem cells can regulate the balance between different immune cell groups or between pro-inflammatory and anti-inflammatory cytokines, and can exert immunity in the ovarian microenvironment by regulating the number of macrophages, regulatory T lymphocytes and related cytokines Regulation characteristics [7].
In addition, mesenchymal stem cells reduced the SOD dismutase in the ovary after transplantation, indicating that the restoration of the ovarian niche may also be due to the regulation of oxidative stress in this microenvironment.

Picture from literature [7]

Picture from literature [7]

Mechanism 4: Anti-fibrosis

Mechanism 4: Anti-fibrosis

After mesenchymal stem cell transplantation, a decrease in collagen levels in the ovary was observed, which indicates that the mechanism of action of these cells in the recovery of ovarian injury may also include anti-fibrosis [8].
In fact, mesenchymal stem cells can inhibit the proliferation of fibroblasts and reduce the deposition of extracellular matrix.
This anti-fibrotic effect is related to some soluble factors, such as HGF, adrenal medulla and basic fibroblast growth factor (BFGF) .

Concluding remarks

Concluding remarks

Ovarian insufficiency is a common disease that affects young women.
It has a great impact on the reproductive ability of these patients, and there is still a lack of effective treatments.
At present, a large number of studies have revealed the potential therapeutic effects of stem cells on premature ovarian failure, and their mechanisms are constantly being revealed.
These are essential for the design of feasible and less invasive clinical programs in the future.
In the future, with the development of more comprehensive and large-scale clinical trials, the clinical application of stem cells in the treatment of premature ovarian failure will be closer to the general public.

references:

references:

[1]Polonio AM, García-Velasco JA, Herraiz S.
Stem Cell Paracrine Signaling for Treatment of Premature Ovarian Insufficiency.
Front Endocrinol (Lausanne).
2021 Feb 24;11:626322.

[1]Polonio AM, García-Velasco JA, Herraiz S.
Stem Cell Paracrine Signaling for Treatment of Premature Ovarian Insufficiency.
Front Endocrinol (Lausanne).
2021 Feb 24;11:626322.

https://pubmed.
ncbi.
nlm.
nih.
gov/33716956/

https://pubmed.
ncbi.
nlm.
nih.
gov/33716956/

[2]Abd-Allah SH, Shalaby SM, Pasha HF, El-Shal AS, Raafat N, Shabrawy SM, Awad HA, Amer MG, Gharib MA, El Gendy EA, Raslan AA, El-Kelawy HM.
Mechanistic action of mesenchymal stem cell injection in the treatment of chemically induced ovarian failure in rabbits.
Cytotherapy.
2013 Jan;15(1):64-75.

[2]Abd-Allah SH, Shalaby SM, Pasha HF, El-Shal AS, Raafat N, Shabrawy SM, Awad HA, Amer MG, Gharib MA, El Gendy EA, Raslan AA, El-Kelawy HM.
Mechanistic action of mesenchymal stem cell injection in the treatment of chemically induced ovarian failure in rabbits.
Cytotherapy.
2013 Jan;15(1):64-75.

https://pubmed.
ncbi.
nlm.
nih.
gov/23260087/

https://pubmed.
ncbi.
nlm.
nih.
gov/23260087/

[3] Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, Epstein SE.
Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms.
Circ Res.
2004 Mar 19;94(5):678-85.

[3] Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, Epstein SE.
Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms.
Circ Res.
2004 Mar 19;94(5):678-85.

https://pubmed.
ncbi.
nlm.
nih.
gov/14739163/

https://pubmed.
ncbi.
nlm.
nih.
gov/14739163/

[4]Xia X, Yin T, Yan J, Yan L, Jin C, Lu C, Wang T, Zhu X, Zhi X, Wang J, Tian L, Liu J, Li R, Qiao J.
Mesenchymal Stem Cells Enhance Angiogenesis and Follicle Survival in Human Cryopreserved Ovarian Cortex Transplantation.
Cell Transplant.
2015;24(10):1999-2010.

[4]Xia X, Yin T, Yan J, Yan L, Jin C, Lu C, Wang T, Zhu X, Zhi X, Wang J, Tian L, Liu J, Li R, Qiao J.
Mesenchymal Stem Cells Enhance Angiogenesis and Follicle Survival in Human Cryopreserved Ovarian Cortex Transplantation.
Cell Transplant.
2015;24(10):1999-2010.

https://pubmed.
ncbi.
nlm.
nih.
gov/25353724/

https://pubmed.
ncbi.
nlm.
nih.
gov/25353724/

[5]Zhang Y, Xia X, Yan J, Yan L, Lu C, Zhu X, Wang T, Yin T, Li R, Chang HM, Qiao J.
Mesenchymal stem cell-derived angiogenin promotes primodial follicle survival and angiogenesis in transplanted human ovarian tissue.
Reprod Biol Endocrinol.
2017 Mar 9;15(1):18.

[5]Zhang Y, Xia X, Yan J, Yan L, Lu C, Zhu X, Wang T, Yin T, Li R, Chang HM, Qiao J.
Mesenchymal stem cell-derived angiogenin promotes primodial follicle survival and angiogenesis in transplanted human ovarian tissue.
Reprod Biol Endocrinol.
2017 Mar 9;15(1):18.

[6]Guo JQ, Gao X, Lin ZJ, Wu WZ, Huang LH, Dong HY, Chen J, Lu J, Fu YF, Wang J, Ma YJ, Chen XW, Wu ZX, He FQ, Yang SL, Liao LM , Zheng F, Tan JM.
BMSCs reduce rat granulosa cell apoptosis induced by cisplatin and perimenopause.
BMC Cell Biol.
2013 Mar 19;14:18.

[6]Guo JQ, Gao X, Lin ZJ, Wu WZ, Huang LH, Dong HY, Chen J, Lu J, Fu YF, Wang J, Ma YJ, Chen XW, Wu ZX, He FQ, Yang SL, Liao LM , Zheng F, Tan JM.
BMSCs reduce rat granulosa cell apoptosis induced by cisplatin and perimenopause.
BMC Cell Biol.
2013 Mar 19;14:18.

https://pubmed.
ncbi.
nlm.
nih.
gov/23510080/

https://pubmed.
ncbi.
nlm.
nih.
gov/23510080/

[7] Yin N, Zhao W, Luo Q, Yuan W, Luan X, Zhang H.
Restoring Ovarian Function With Human Placenta-Derived Mesenchymal Stem Cells in Autoimmune-Induced Premature Ovarian Failure Mice Mediated by Treg Cells and Associated Cytokines.
Reprod Sci .
2018 Jul;25(7):1073-1082.

[7] Yin N, Zhao W, Luo Q, Yuan W, Luan X, Zhang H.
Restoring Ovarian Function With Human Placenta-Derived Mesenchymal Stem Cells in Autoimmune-Induced Premature Ovarian Failure Mice Mediated by Treg Cells and Associated Cytokines.
Reprod Sci .
2018 Jul;25(7):1073-1082.

https://pubmed.
ncbi.
nlm.
nih.
gov/28954601/

https://pubmed.
ncbi.
nlm.
nih.
gov/28954601/

[8]Wang Z, Wang Y, Yang T, Li J, Yang X.
Study of the reparative effects of menstrual-derived stem cells on premature ovarian failure in mice.
Stem Cell Res Ther.
2017 Jan 23;8(1): 11.
doi: 10.
1186/s13287-016-0458-1.
Erratum in: Stem Cell Res Ther.
2017 Mar 8;8(1):49.

[8]Wang Z, Wang Y, Yang T, Li J, Yang X.
Study of the reparative effects of menstrual-derived stem cells on premature ovarian failure in mice.
Stem Cell Res Ther.
2017 Jan 23;8(1): 11.
doi: 10.
1186/s13287-016-0458-1.
Erratum in: Stem Cell Res Ther.
2017 Mar 8;8(1):49.

https://pubmed.
ncbi.
nlm.
nih.
gov/28114977/

https://pubmed.
ncbi.
nlm.
nih.
gov/28114977/