Spermatogonial stem cell

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The fates of spermatogonial stem cells: renewal or differentiation Spermatocytogenesis.png
The fates of spermatogonial stem cells: renewal or differentiation

A spermatogonial stem cell (SSC), also known as a type A spermatogonium, is a spermatogonium that does not differentiate into a spermatocyte, a precursor of sperm cells. Instead, they continue dividing into other spermatogonia or remain dormant to maintain a reserve of spermatogonia. Type B spermatogonia, on the other hand, differentiate into spermatocytes, which in turn undergo meiosis to eventually form mature sperm cells. [1] [2] [3]

Contents

Spermatogonial stem cells in the testis

During fetal development, gonocytes develop from primordial germ cells , and following this SSCs develop from gonocytes in the testis. [4] SSCs are the early precursor for spermatozoa and are responsible for the continuation of spermatogenesis in adult mammals. The stem cells are capable of dividing into more SSCs which is vital for maintaining the stem cell pool. Alternatively, they go on to differentiate into spermatocytes, spermatids , and finally spermatozoa.

One SSC is the precursor for multiple spermatozoa and therefore SSCs are much less numerous in the testes than cells undergoing spermatogenesis. [5] [6] [7] [8] [9] [10]

Nomenclature

In humans

Undifferentiated spermatogonia can be split into 2 groups; A Dark (Ad) and A Pale (Ap)

Ad spermatogonia are reserve stem cells. These cells can divide to produce more SSCs but usually do not. Ap spermatogonia are actively dividing to maintain the stem cell pool. B1-B4 spermatogonia encompass the differentiating spermatogonia and are no longer considered to be stem cells.

Most research into SSCs has been carried out in rodents. The subtypes of spermatogonia differ between mice and humans. [11] [12] [13]

In mice

A Single (As) spermatogonia is capable of creating 2 separate daughter SSCs when they divide or the daughter cells can join and form A Paired (Apr) spermatogonia.

Both As and Apr spermatogonia are undifferentiated. Chains of these cells form and are referred to as A Aligned (Aal). Aal spermatogonia differentiate and thus are no longer classed as stem cells. They go on to divide 6 times eventually forming B-type spermatogonia.

SSC Niche

The most important somatic cells that support the regulation of SSCs are Sertoli cells. Various other somatic cells in the interstitial tissue support Sertoli cells such as Leydig cells and peritubular myoid cells therefore indirectly influencing SSCs and the location of their niche. [14]

Spermatogonia stem cells in mammals are found between the basal membrane of the seminiferous tubules and the Sertoli cells. They remain here until the meiotic prophase stage of meiosis. Here the spermatocytes pass through the basal membrane via the sertoli cell barrier.

SSCs stay within their niche where they are encouraged to self-renew. When they move past the basal membrane they differentiate due to cell signals. [15] [16] [17] [18] [19]

Paracrine regulation of SSC self-renewal

Local signals regulate the self-renewal of spermatogonial stem cells (SSCs). [20] Around 50% of the SSC population undergo self-renewal to maintain stem cell numbers, and the other 50% become committed progenitor cells that will differentiate into spermatozoa during spermatogenesis. [21] Cells present in the testes express molecules that play key roles in the regulation of SSC self-renewal. In mice, Sertoli cells have been shown to secrete Glial cell line-derived neurotrophic factor (GDNF) which has a stimulatory effect on stem cell self-renewal. This factor is thought to be expressed in the peritubular cells in human testes. [4] Fibroblast growth factor (FGF2) is another molecule crucial for the regulation of stem cell renewal and is expressed in Sertoli cells, Leydig cells, and germ cells. FGF2 signaling interacts with GDNF to enhance the proliferation rate. [4] Chemokine (C-X-C motif) ligand 12 (CXCL12) signaling via its receptor C-X-C chemokine receptor type 4 (CXCR4) is also involved in the regulation of SSC fate decisions.CXCL12 is found in Sertoli cells in the basement membrane of the seminiferous tubules in adult mouse testes, and its receptor is expressed in undifferentiated spermatogonial cells. [22]

GDNF and FGF2 are both required to activate the phosphoinositide 3-kinase (PI3K)-Akt pathway, and the mitogen-activated protein kinase/ERK1 kinase1 (MEK) pathway, which potentiates SSC proliferation and survival. [23] CXCL12, FGF2, and GDNF all communicate via a network to mediate SSC functions. [22]

Differentiation

Spermatogonial stem cells are the precursors to spermatozoa, which are produced through a series of differentiation steps. [4] This is the alternative SSC outcome to self-renewal. SSCs survive within microenvironments, termed niches, which provide extrinsic stimuli that drive stem cell differentiation or self-renewal. [24] The SSC niche is found in the seminiferous epithelium of mammalian testis and is primarily constituted of Sertoli and peritubular myoid cells. [22]

There are two primary differentiation stages, the first of which involves transforming As (single) spermatogonia into daughter progeny Apr (paired) spermatogonia, which are predestined to differentiate. These can divide further to create Aal (A-aligned) spermatogonia. [4]

The second step involves the production of differentiating A1 spermatogonia from Apr or Aal spermatogonia. These A1 spermatogonia undergo a further five divisions to produce A2, A3, A4, intermediate, and type B spermatogonia, which can enter meiosis I. [4]

It takes around 64 days to produce mature spermatozoa from differentiating SSCs, and 100 million spermatozoa can be produced each day. [22]

One of the major known substances driving the differentiation of SSCs, and therefore the production of spermatozoa, is Retinoic Acid (RA). [14] There are theories supporting the hypotheses of both an indirect (via Sertoli cells) or a direct pathway. [4]

It is thought that Sertoli cells produce RA through the conversion of circulating retinol to retinal and then finally to RA. [14] Exposure to RA drives cellular differentiation into A1 spermatogonia and is implicated in further meiotic differentiation. [4] As a result of differentiation, the genes required to maintain an SSC state are no longer expressed. [14]

Male reproductive function declines with increasing age as indicated by decreased sperm quality and fertility. [25] As rats age, undifferentiated spermatogonial cells undergo numerous changes in gene expression. [26] These changes include upregulation of several genes involved in the DNA damage response. This finding suggests that during aging there is an increase in DNA damage leading to an upregulation of DNA damage response proteins to help repair these damages. [26] Thus it appears that reproductive aging originates in undifferentiated spermatogenic cells. [26]

Isolation and culture

SSCs have the potential to become increasingly clinically relevant in treating sterility (in vitro spermatogenesis) and preserving fertility before gonadotoxic treatments. [27] To this aim, SSCs must be reliably isolated from testicular biopsies e.g. expansion and purification. Current protocols include magnetic-activated cell sorting (MACS) and fluorescence-activated cell sorting (FACS) based on positive SSC cellular markers such as CD90 [28] and FGFR3 [29] in combination with negative markers like CD45. [28] The latter is particularly important in excluding malignant cells from cancer patients’ biopsies.

Once isolated, SSC populations are cultured for amplification, characterization, line maintenance, and potentially in vitro spermatogenesis or genomic editing. [30] The main challenges to SSC culturing are the interactions between media substances and the epigenetic makeup that underlies pluripotency and can affect future offspring. Short-term in vitro propagation of these cells has been carried out in Stem-Pro 34 media supplemented by growth factors. [31] The long-term culture of human SSCs is not established yet, however, one group reports successful proliferation in feeder cell-free media supplied with growth factors and hydrogel. [32]

Transplantation

The first successful SSC transplantation was described in mice in 1994 whereby the procedure restored spermatogenesis fully in an otherwise infertile mouse. [33] These mice were then able to produce viable offspring which opened new exciting doors for future potential therapies in humans.

As cancer treatments are not cancer cell-specific and are often gonadotoxic (toxic to the ovaries and the testes), children usually face infertility as a consequence of treatment as there is no established way to preserve their fertility yet, especially in prepubertal boys. Infertility after cancer treatment depends on the type and dosage of treatment but can vary from 17% to 82% of patients. [34] Spermatogonial stem cell therapy (SSCT) has been proposed as a potential method to restore fertility in cancer survivors who desire to have children later in life. The method has been tested in numerous animal models including non-human primates; Hermann et al. [35] took out and isolated SSCs from prepubertal and adult rhesus macaques before treating them with busulfan (an alkylating agent used in chemotherapy). SSCs were then injected back into the rete testis of the same animal that they were taken from ~10–12 weeks after treatment, and spermatogenesis was observed in almost all recipients (16/17). However, these SSCs were difficult to detect which is why further analysis of the ability of descendant sperm to fertilize could not be determined. The viability of embryos fertilized by donor sperm after SSC transplantation needs to be evaluated to truly determine the usefulness of this technique.

Recently, SSC transplantation has also been proposed as a potential method for the conservation of endangered species through xenogeneic transplantation. Roe et al. [36] suggested that the reproductive lifespan of such species could be extended by transplanting their germ cells into a domestic host. In their study, they used the quail as a model for an exotic species and transplanted SSCs into chicken embryos which successfully colonized the gonadal ridge of the host embryo. This allows the isolation of mature sperm later on in development from the host even after the donor has deceased which can be used in future fertilization and potentially more successful conservation. [37]

Related Research Articles

<span class="mw-page-title-main">Gametogenesis</span> Biological process

Gametogenesis is a biological process by which diploid or haploid precursor cells undergo cell division and differentiation to form mature haploid gametes. Depending on the biological life cycle of the organism, gametogenesis occurs by meiotic division of diploid gametocytes into various gametes, or by mitosis. For example, plants produce gametes through mitosis in gametophytes. The gametophytes grow from haploid spores after sporic meiosis. The existence of a multicellular, haploid phase in the life cycle between meiosis and gametogenesis is also referred to as alternation of generations.

<span class="mw-page-title-main">Germ cell</span> Gamete-producing cell

A germ cell is any cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate in the primitive streak and migrate via the gut of an embryo to the developing gonads. There, they undergo meiosis, followed by cellular differentiation into mature gametes, either eggs or sperm. Unlike animals, plants do not have germ cells designated in early development. Instead, germ cells can arise from somatic cells in the adult, such as the floral meristem of flowering plants.

<span class="mw-page-title-main">Spermatogenesis</span> Production of sperm

Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testicle. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubules. These cells are called spermatogonial stem cells. The mitotic division of these produces two types of cells. Type A cells replenish the stem cells, and type B cells differentiate into primary spermatocytes. The primary spermatocyte divides meiotically into two secondary spermatocytes; each secondary spermatocyte divides into two equal haploid spermatids by Meiosis II. The spermatids are transformed into spermatozoa (sperm) by the process of spermiogenesis. These develop into mature spermatozoa, also known as sperm cells. Thus, the primary spermatocyte gives rise to two cells, the secondary spermatocytes, and the two secondary spermatocytes by their subdivision produce four spermatozoa and four haploid cells.

<span class="mw-page-title-main">Seminiferous tubule</span> Location of meiosis and creation of spermatozoa

Seminiferous tubules are located within the testicles, and are the specific location of meiosis, and the subsequent creation of male gametes, namely spermatozoa.

<span class="mw-page-title-main">Sertoli cell</span> Cells found in human testes which help produce sperm

Sertoli cells are a type of sustentacular "nurse" cell found in human testes which contribute to the process of spermatogenesis as a structural component of the seminiferous tubules. They are activated by follicle-stimulating hormone (FSH) secreted by the adenohypophysis and express FSH receptor on their membranes.

<span class="mw-page-title-main">Spermatocyte</span> Sperm precursor cell that undergoes meiosis

Spermatocytes are a type of male gametocyte in animals. They derive from immature germ cells called spermatogonia. They are found in the testis, in a structure known as the seminiferous tubules. There are two types of spermatocytes, primary and secondary spermatocytes. Primary and secondary spermatocytes are formed through the process of spermatocytogenesis.

Reproductive biology includes both sexual and asexual reproduction.

<span class="mw-page-title-main">Spermatogonium</span> Undifferentiated male germ cell

A spermatogonium is an undifferentiated male germ cell. Spermatogonia undergo spermatogenesis to form mature spermatozoa in the seminiferous tubules of the testis.

<span class="mw-page-title-main">Sperm</span> Male reproductive cell in anisogamous forms of sexual reproduction

Sperm is the male reproductive cell, or gamete, in anisogamous forms of sexual reproduction. Animals produce motile sperm with a tail known as a flagellum, which are known as spermatozoa, while some red algae and fungi produce non-motile sperm cells, known as spermatia. Flowering plants contain non-motile sperm inside pollen, while some more basal plants like ferns and some gymnosperms have motile sperm.

Gametogonium are stem cells for gametes located within the gonads. They originate from primordial germ cells, which have migrated to the gonads. Male gametogonia which are located within the testes during development and adulthood are called spermatogonium. Female gametogonia, known as oogonium, are found within the ovaries of the developing foetus and were thought to be depleted at or after birth. Spermatogonia and oogonia are classified as sexually differentiated germ cells.

<span class="mw-page-title-main">Spermatocytogenesis</span> Division of stem cells leading to sperm

Spermatocytogenesis is the male form of gametocytogenesis and involves stem cells dividing to replace themselves and to produce a population of cells destined to become mature sperm.

Spermatogenesis arrest is known as the interruption of germinal cells of specific cellular type, which elicits an altered spermatozoa formation. Spermatogenic arrest is usually due to genetic factors resulting in irreversible azoospermia. However some cases may be consecutive to hormonal, thermic, or toxic factors and may be reversible either spontaneously or after a specific treatment. Spermatogenic arrest results in either oligospermia or azoospermia in men. It is quite a difficult condition to proactively diagnose as it tends to affect those who have normal testicular volumes; a diagnosis can be made however through a testicular biopsy.

In developmental biology, the cells that give rise to the gametes are often set aside during embryonic cleavage. During development, these cells will differentiate into primordial germ cells, migrate to the location of the gonad, and form the germline of the animal.

Stem-cell niche refers to a microenvironment, within the specific anatomic location where stem cells are found, which interacts with stem cells to regulate cell fate. The word 'niche' can be in reference to the in vivo or in vitro stem-cell microenvironment. During embryonic development, various niche factors act on embryonic stem cells to alter gene expression, and induce their proliferation or differentiation for the development of the fetus. Within the human body, stem-cell niches maintain adult stem cells in a quiescent state, but after tissue injury, the surrounding micro-environment actively signals to stem cells to promote either self-renewal or differentiation to form new tissues. Several factors are important to regulate stem-cell characteristics within the niche: cell–cell interactions between stem cells, as well as interactions between stem cells and neighbouring differentiated cells, interactions between stem cells and adhesion molecules, extracellular matrix components, the oxygen tension, growth factors, cytokines, and the physicochemical nature of the environment including the pH, ionic strength and metabolites, like ATP, are also important. The stem cells and niche may induce each other during development and reciprocally signal to maintain each other during adulthood.

Gonocytes are the precursors of spermatogonia that differentiate in the testis from primordial germ cells around week 7 of embryonic development and exist up until the postnatal period, when they become spermatogonia. Despite some uses of the term to refer to the precursors of oogonia, it was generally restricted to male germ cells. Germ cells operate as vehicles of inheritance by transferring genetic and epigenetic information from one generation to the next. Male fertility is centered around continual spermatogonia which is dependent upon a high stem cell population. Thus, the function and quality of a differentiated sperm cell is dependent upon the capacity of its originating spermatogonial stem cell (SSC).

<span class="mw-page-title-main">Peritubular myoid cell</span> Smooth muscle cell found in testis

A peritubular myoid (PTM) cell is one of the smooth muscle cells which surround the seminiferous tubules in the testis. These cells are present in all mammals but their organization and abundance varies between species. The exact role of PTM cells is still somewhat uncertain and further work into this is needed. However, a number of functions of these cells have been established. They are contractile cells which contain actin filaments and are primarily involved in transport of spermatozoa through the tubules. They provide structural integrity to the tubules through their involvement in laying down the basement membrane. This has also been shown to affect Sertoli cell function and PTM cells also communicate with Sertoli cells through the secretion of growth factors and ECM components. Studies have shown PTM cells to be critical in achieving normal spermatogenesis. Overall, PTM cells have a role in both maintaining the structure of the tubules and regulating spermatogenesis through cellular interaction.

In vitro spermatogenesis is the process of creating male gametes (spermatozoa) outside of the body in a culture system. The process could be useful for fertility preservation, infertility treatment and may further develop the understanding of spermatogenesis at the cellular and molecular level. 

Spermatogenesis-associated protein 16 is a mammalian protein encoded by the SPATA16 gene. SPATA16, also known as NYD-SP12, is a developmental protein that aids in differentiation of germ cells for spermatogenesis and participates in acrosome formation for appropriate sperm-egg fusion. SPATA16 is located on chromosome 3 at position 26.31 and is a member of the tetratricopeptide repeat-like superfamily, which facilitate interactions and assemblies between proteins and protein complexes.

<span class="mw-page-title-main">Side effects of radiotherapy on fertility</span>

The side effects of radiotherapy on fertility are a growing concern to patients undergoing radiotherapy as cancer treatments. Radiotherapy is essential for certain cancer treatments and often is the first point of call for patients. Radiation can be divided into two categories: ionising radiation (IR) and non-ionising radiation (NIR). IR is more dangerous than NIR and a source of this radiation is X-rays used in medical procedures, for example in radiotherapy.

The germ cell nest forms in the ovaries during their development. The nest consists of multiple interconnected oogonia formed by incomplete cell division. The interconnected oogonia are surrounded by somatic cells called granulosa cells. Later on in development, the germ cell nests break down through invasion of granulosa cells. The result is individual oogonia surrounded by a single layer of granulosa cells. There is also a comparative germ cell nest structure in the developing spermatogonia, with interconnected intracellular cytoplasmic bridges.

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