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In today’s open access paper, researchers discuss the evidence for the existence of germline stem cells in the ovaries, responsible for maintaining fertility in the usual manner of stem cells, by generating daughter cells that replace losses and ensure function. Is ovarian aging, leading into age-related infertility, much accelerated over the aging of other organs in our species because this stem cell population loses function more rapidly than those in other tissues? That is a reasonable hypothesis, and some of the possible mechanisms are discussed. That overies are a hypoxic environment to begin with, and that supply of oxygen and nutrients does tend to decline with age for a range of reasons, is one of the more intriguing ideas.
A number of groups, including a few biotech startups in the growing longevity industry, appear to believe that ovarian aging is a good place to start on the development of the next generation of regenerative medicine, deploying more sophisticated approaches to either replace stem cell populations or rejuvenate existing populations and their damaged niches. In part this is because such therapies would be targeted to people who are not very old, are more robust and resilient. In part it is because the understanding of ovarian tissue and cell function has reached a tipping point: we are past the point at which researchers have constructed artificial ovaries and demonstrated that they are functional following transplantation into mice, for example. Techniques that succeed in restoring ovarian function could generalize to other stem cell populations. This may or may not come to pass, depending on how much of a special case ovarian aging turns out to be, but we can hope.
Female germline stem cells: aging and anti-aging
The underlying mechanisms for the aging of the ovary are still poorly understood, partially because it is a complex biological process in which many factors interact internally and externally. Compared with the “evergreen” male testes, female ovaries in advanced age women are more like “rotten root of old tree”. What makes this big different? The researchers believe that the female germline stem cells (FGSCs) aging directly determines the ovarian aging. In physiological conditions, when women reach their advanced age, the stem cells in their ovaries are exhausted, they face menopause and symptoms of hypoestrogenism, while males enjoy their old age life without dramatic decline of their testes function. They still have the ability to father as long as their spouses are young enough.
Whether mammal’s ovaries have FGSCs to supplement the original follicle pool after birth has been debated for nearly one century. Now, however, scientists have isolated cells that could be subcultured in vitro and express the both stem and germ cell-specific protein markers in mice, adult mice, rats, and human ovarian tissue cortex respectively. Using a variety of methods, including stem cell culture and expansion, stem cell transplantation, genetic modification and gene editing, in vivo cell lineage tracking, the researchers confirmed existence of FGSCs in the postnatal ovaries in a variety of mammals, including humans, even old women ovarian surface epithelium, and observed that FGSCs had the ability to direct differentiation into eggs, continuously replenish follicle pools, and restore progeny to infertile model. FGSCs with GFP were transplanted into infertile mice, and both mature follicles with GFP and offspring with GFP were is covered obtained, which provided the most direct evidence of FGSCs existence.
Accumulating evidence suggest the FGSCs niche is the key link to ovarian failure. The FGSCs niche might be more important than aging of FGSCs themselves. The niche of ovaries in mammals maybe includes follicular membrane–stromal cells, granulosa cells, extracellular matrix, blood vessels, immune system-related cells and cytokines. Transplanting niche cells (mainly refer to Sertoli or mesenchymal cells) can regenerate the non-functional gonads, and this approach has resulted in the birth of fertile offspring in mice. The stem cell niche, combined with exogenous microenvironment alterations, such as changes from oxygen tension, temperature, hormones or cytokines from blood supplement, results in restricted self-renewal, senescence, skewed differentiation and compromised regeneration.
In the exogenous microenvironment, special focus has to be placed on the role of hypoxia in inducing and accelerating stem cell aging. Hypoxia, the unbalance between oxygen supply and demand, is the primary culprit of oxidative stress and chronic inflammation. Unfortunately, ovary is a deeply hypoxic organ due to it’s unique structure and cell composition. On the one hand, with the growth and progression of follicular oocytes and the proliferation and division of granulosa cells, the oxygen demand gradually increases. On the other hand, continuous ovulation results in the increase of fibrous connective tissue and the significant reduction of blood vessels in the ovary, which leads to the decrease of oxygen supply in the ovary, and the decrease of blood vessels and blood supply in the ovary with the increase of age. In addition, chronic, low-grade inflammatory response caused by repeated ovulation and the accompanying oxidative stress aggravate the imbalance between supply and demand, resulting in low oxygen concentration in the ovary. This may be the important reason that the speed of ovarian aging should be faster than other organs.
In summary, exploring the mechanism of FGSCs aging is helpful in solving female infertility fundamentally in clinical practice. Rebuilding niches of FGSCs, regulation of immune dysfunction, anti-inflammation, and oxidative stress remission are expected to restore or replenish FGSCs, ultimately to delay ovarian aging.