LONGECITY

Experiments in mouse models show the efficacy and safety of mesenchymal stem cell transplantation in treating ovarian aging [1].

Mesenchymal stem cells as a therapy

Mesenchymal stem cells (MSCs) are stem cells derived from mesodermal tissue, such as the umbilical cord, umbilical cord blood, the placenta, fat tissue, and bone marrow [2]. MSCs are a promising new therapeutic approach for various diseases [3], including this paper’s focus: female infertility caused by ovarian aging.

The quantity and quality of oocytes start to decline relatively early in a female’s life. [4] Since contemporary women frequently postpone motherhood, the number of females diagnosed with infertility increases. [5]

At this moment, MSC therapy for human ovaries is in the preliminary stage of clinical application [6, 7]. Studies to date have focused on women with premature ovarian failure and ovarian hyporesponsiveness and used MSCs derived from their own bodies.

The efficacy of MSCs

The difference between this study and the previous mouse study is that in previous studies, stem cells were injected through the animals’ tail veins, which required cells to travel from the site of injection to the ovaries. In this study, the researchers used orthotopic transplantation, which allows the cells to be delivered closer to the site of their action to increase efficiency.

Among other groups, the researchers used young (4-5 months) mice and aged (10-12 months) mice, which had reduced reproductive functions, in order to evaluate the efficacy and toxicity of MSC treatment. MSCs were derived from healthy donors’ fat tissue (adipose tissue, AD) obtained during liposuction surgery and from full-term umbilical cord (UC) tissue following neonatal delivery. The researchers observed improved ovarian functioning in aging mice when AD-MSCs and UC-MSCs were used. However, AD-MSCs were shown to be more effective than UC-MSCs.

Following the injection of MSCs, the mice were monitored for eight days to track their oestrous cycle, the murine equivalent of monthly hormonal changes in human females. MSC transplantation improved this cycle compared to the control animals. For UC-MSCs, the changes in the duration of cycle phases were statistically significant, but for AD-MSCs, they were not.

After 1 and 3 weeks following the transplantation, the mice were sacrificed, and their tissues were analyzed. Analysis of the ovaries revealed that old mice that received AD-MSCs had a significantly increased proportion of proliferating cells compared to controls. UC-MSCs led to a slight increase in the proportion of proliferating cells, but it wasn’t statistically significant.

MSC ovarian transplantation didn’t increase the total number of follicles, which contain immature egg cells, in the ovaries. Still, the number of primary follicles significantly increased after UC-MSC and AD-MSC transplantation compared to controls. Also, both types of stem cells increased blood vessel proliferation in older animals’ ovaries.

An analysis of gene expression showed that UC-MSC and AD-MSC transplantation led to increased expression of MAPK cascade components, “central signaling pathways that regulate a wide variety of stimulated cellular processes, including proliferation, differentiation, apoptosis and stress response” [8]. AD-MSCs caused more changes in gene expression than UC-MSCs, including “cell-cell adhesion and positive regulation of the immune response.” The researchers also observed that these treatments had different short-term and long-term effects. While short-term effects involved different signaling pathways, “long-term effects were enriched in the activation of immune function.“

Good safety profile

Since the treatment’s efficacy showed promising results, the next step was to assess the safety of these transplants, which is indispensable in assessing theiir clinical utility.

Analyzing the mice sacrificed in this experiment indicated that they appeared healthy and that the transplanted MSCs did not generate tumors. Similarly, toxicity testing showed that “there was no significant acute toxic reaction” following MSC transplantation. Additionally, the expression of immune molecules wasn’t significantly increased, and the number of immune cells didn’t significantly increase in most mice. This data suggests that AD-MSC and UC-MSC transplantation does not significantly stimulate the immune system.

To function properly, orthotopically transplanted cells must reach their destination and not accumulate somewhere else in the body. The researchers injected a few mice with fluorescently labeled cells, and then searched the mice’s organs for these clearly visible cells after sacrifice. These cells accumulated mainly in the ovaries, with a small number of cells also observed in the uterus and spleen.

Therapy that holds potential

Based on the results of their experiments, the authors believe that MSCs hold great potential for clinical applications. Since they can be produced industrially, they can benefit many patients. However, first, the efficacy and safety of MSCs need to be shown during clinical trials.

Safety validation experiments confirmed that both AD-MSCs and UC-MSCs were not tumorigenic, with no acute toxic reactions, low immunogenicity, and a small amount of nondeterministic distribution. Furthermore, the mechanisms underlying the long-term and short-term effects after MSC transplantation differed, yet both led to an enhancement of the MAPK cascade. Collectively, orthotopic transplantation of MSCs has significant efficacy and high safety in the treatment of ovarian ageing.

Literature

[1] Pei, W., Fu, L., Guo, W., Wang, Y., Fan, Y., Yang, R., Li, R., Qiao, J., & Yu, Y. (2024). Efficacy and safety of mesenchymal stem cell therapy for ovarian ageing in a mouse model. Stem cell research & therapy, 15(1), 96.

[2] Kouroupis, D., Sanjurjo-Rodriguez, C., Jones, E., & Correa, D. (2019). Mesenchymal Stem Cell Functionalization for Enhanced Therapeutic Applications. Tissue engineering. Part B, Reviews, 25(1), 55–77.

[3] Galipeau, J., & Sensébé, L. (2018). Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities. Cell stem cell, 22(6), 824–833.

[4] Secomandi, L., Borghesan, M., Velarde, M., & Demaria, M. (2022). The role of cellular senescence in female reproductive aging and the potential for senotherapeutic interventions. Human reproduction update, 28(2), 172–189.

[5] Carson, S. A., & Kallen, A. N. (2021). Diagnosis and Management of Infertility: A Review. JAMA, 326(1), 65–76.

[6] Herraiz, S., Romeu, M., Buigues, A., Martínez, S., Díaz-García, C., Gómez-Seguí, I., Martínez, J., Pellicer, N., & Pellicer, A. (2018). Autologous stem cell ovarian transplantation to increase reproductive potential in patients who are poor responders. Fertility and sterility, 110(3), 496–505.e1.

[7] Yan, L., Wu, Y., Li, L., Wu, J., Zhao, F., Gao, Z., Liu, W., Li, T., Fan, Y., Hao, J., Liu, J., & Wang, H. (2020). Clinical analysis of human umbilical cord mesenchymal stem cell allotransplantation in patients with premature ovarian insufficiency. Cell proliferation, 53(12), e12938.

[8] Plotnikov, A., Zehorai, E., Procaccia, S., & Seger, R. (2011). The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochimica et biophysica acta, 1813(9), 1619–1633.