"Adipose-derived mesenchymal stem cell therapy for the management of female sexual dysfunction: Literature reviews and study design of a clinical trial"

Abstract

Hormone imbalance and female sexual dysfunction immensely affect perimenopausal female health and quality of life. Hormone therapy can improve female hormone deficiency, but long-term use increases the risk of cardiovascular diseases and cancer. Therefore, it is necessary to develop a novel effective treatment to achieve long-term improvement in female general and sexual health. This study reviewed factors affecting syndromes of female sexual dysfunction and its current therapy options. Next, the authors introduced research data on mesenchymal stromal cell/mesenchymal stem cell (MSC) therapy to treat female reproductive diseases, including Asherman's syndrome, premature ovarian failure/primary ovarian insufficiency, and vaginal atrophy. Among adult tissue-derived MSCs, adipose tissue-derived stem cells (ASCs) have emerged as the most potent therapeutic cell therapy due to their abundant presence in the stromal vascular fraction of fat, high proliferation capacity, superior immunomodulation, and strong secretion profile of regenerative factors. Potential mechanisms and side effects of ASCs for the treatment of female sexual dysfunction will be discussed. Our phase I clinical trial has demonstrated the safety of autologous ASC therapy for women and men with sexual hormone deficiency. We designed the first randomized controlled crossover phase II trial to investigate the safety and efficacy of autologous ASCs to treat female sexual dysfunction in perimenopausal women. Here, we introduce the rationale, trial design, and methodology of this clinical study. Because aging and metabolic diseases negatively impact the bioactivity of adult-derived MSCs, this study will use ASCs cultured in physiological oxygen tension (5%) to cope with these challenges. A total of 130 perimenopausal women with sexual dysfunction will receive two intravenous infusions of autologous ASCs in a crossover design. The aims of the proposed study are to evaluate 1) the safety of cell infusion based on the frequency and severity of adverse events/serious adverse events during infusion and follow-up and 2) improvements in female sexual function assessed by the Female Sexual Function Index (FSFI), the Utian Quality of Life Scale (UQOL), and the levels of follicle-stimulating hormone (FSH) and estradiol. In addition, cellular aging biomarkers, including plasminogen activator inhibitor-1 (PAI-1), p16 and p21 expression in T cells and the inflammatory cytokine profile, will also be characterized. Overall, this study will provide essential insights into the effects and potential mechanisms of ASC therapy for perimenopausal women with sexual dysfunction. It also suggests direction and design strategies for future research.

Keywords: ASCs (adipose stem cells); adipose-derived mesenchymal stem cells; cell therapy; female sexual dysfunction; menopause; regenerative medicine; sexual function impairment.

FIGURE 1

Overview of physical and emotional changes in perimenopausal women. Menopause is a natural aging process and marks enormous changes in both the general and sexual life of women. These include sex hormone imbalance, impaired immune system, increased inflammation, altered metabolism, and psychological changes. These changes can lead to accelerated organ degeneration and increased risks of musculoskeletal diseases, cardiovascular complications, metabolic diseases, and sexual dysfunction.

FIGURE 2

Potential mechanisms of ASCs. ASCs might act through multiple mechanisms to improve the functions of the female reproductive system. The cells can home and be retained in the reproductive tract for a short time. In the ovary, they differentiate into theca cells and form basal lamina to support oocyte development. In the uterus, ASCs give rise to stromal and epithelial cells of the endometrium. Similar to MSCs from other tissue sources, ASCs exhibit a profound secretome and immune regulation activity. The cells secrete many growth factors, cytokines, and miRNAs in the form of both soluble proteins and extracellular vesicles. Growth factors, such as HGF, VEGF, IGF, FGF-2, EGF, GFNF, and BDNF, trigger cell proliferation, inhibit apoptosis, and promote wound healing in many organs, including the reproductive system. VEGF, PDGF, HGF, Ang-1 and Ang-2 orchestrate angiogenesis. Moreover, ASCs produce many strong anti-inflammatory factors, such as PGE2, IDO, TGF-β, and PD-L1, to regulate immune cells. ASCs inhibit Th1-cell proliferation and promote regulatory T-cell differentiation. They induce quiescence of B cells and alter antibody production. They shift macrophages from a proinflammatory M1 to an anti-inflammatory M2 phenotype and interfere with dendritic cell maturation. Hence, ASCs might reverse the aging process by restoring reproductive organ functions and increasing estradiol levels, modulating the immune system, and reducing inflammation.

FIGURE 3

Research diagram. A total of 130 enrolled patients will be randomly assigned to two groups: group A will receive two infusions of autologous ASCs at day 0 and day 90 ± 7; group B will receive two infusions of autologous ASCs at day 180 ± 14 and day 270 ± 14. All patients will be monitored for 12 months after the first cell infusion. During this period, AEs will be recorded every week after the ASC infusions and every month in the next months by the study team. Patient visit schedules are depicted, in which physical examination, laboratory tests and FSFI and UQOL questionnaires will be administered. Furthermore, cytokine profiles will be analyzed at baseline and on days 30 ± 2, 90 ± 7, and 180 ± 14. Cellular aging biomarkers will be quantified at baseline and at 180 ± 14 and 365 ± 14.