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 (e.g. Ca2+ concentration) 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.
Scientists are studying the various components of the niche and trying to replicate the in vivo niche conditions in vitro. This is because for regenerative therapies, cell proliferation and differentiation must be controlled in flasks or plates, so that sufficient quantity of the proper cell type are produced prior to being introduced back into the patient for therapy.
Human embryonic stem cells are often grown in fibrotastic growth factor-2 containing, fetal bovine serum supplemented media. They are grown on a feeder layer of cells, which is believed to be supportive in maintaining the pluripotent characteristics of embryonic stem cells. However, even these conditions may not truly mimic in vivo niche conditions.
Adult stem cells remain in an undifferentiated state throughout adult life. However, when they are cultured in vitro, they often undergo an 'aging' process in which their morphology is changed and their proliferative capacity is decreased. It is believed that correct culturing conditions of adult stem cells needs to be improved so that adult stem cells can maintain their stemness over time.
A Nature Insight review defines niche as follows:
History Though the concept of stem cell niche was prevailing in vertebrates, the first characterization of stem cell niche in vivo was worked out in Drosophila germinal development.
The architecture of the stem-cell niche By continuous intravital imaging in mice, researchers were able to explore the structure of the stem cell niche and to obtain the fate of individual stem cells (SCs) and their progeny over time in vivo. In particular in intestinal crypt, two distinct groups of SCs have been identified: the "border stem cells" located in the upper part of the niche at the interface with transit amplifying cells (TAs), and "central stem cells" located at the crypt base. The proliferative potential of the two groups was unequal and correlated with the cells' location (central or border). It was also shown that the two SC compartments acted in accord to maintain a constant cell population and a steady cellular turnover. A similar dependence of self-renewal potential on proximity to the niche border was reported in the context of hair follicle, in an in vivo live-imaging study.
This bi-compartmental structure of stem cell niche has been mathematically modeled to obtain the optimal architecture that leads to the maximum delay in double-hit mutant production. They found that the bi-compartmental SC architecture minimizes the rate of two-hit mutant production compared to the single SC compartment model. Moreover, the minimum probability of double-hit mutant generation corresponds to purely symmetric division of SCs with a large proliferation rate of border stem cells along with a small, but non-zero, proliferation rate of central stem cells.
Stem cell niches harboring continuously dividing cells, such as those located at the base of the intestinal gland, are maintained at small population size. This presents a challenge to the maintenance of multicellular tissues, as small populations of asexually dividing individuals will accumulate deleterious mutations through genetic drift and succumb to mutational meltdown. Mathematical modeling of the intestinal gland reveals that the small population size within the stem cell niche minimizes the probability of carcinogenesis occurring anywhere, at the expense of gradually accumulated deleterious mutations throughout organismal lifetime—a process that contributes to tissue degradation and aging. Therefore, the population size of the stem cell niche represents an evolutionary trade-off between the probability of cancer formation and the rate of aging.
Examples
Germline
Germline stem cells (GSCs) are found in organisms that continuously produce sperm and eggs until they are sterile. These specialized stem cells reside in the GSC niche, the initial site for gamete production, which is composed of the GSCs, somatic stem cells, and other somatic cells. In particular, the GSC niche is well studied in the genetic model organism Drosophila melanogaster and has provided an extensive understanding of the molecular basis of stem cell regulation.
GSC niche in Drosophila ovaries In Drosophila melanogaster, the GSC niche resides in the anterior-most region of each ovariole, known as the germarium. The GSC niche consists of necessary somatic cells-terminal filament cells, cap cells, escort cells, and other stem cells which function to maintain the GSCs. The GSC niche holds on average 2–3 GSCs, which are directly attached to somatic cap cells and Escort stem cells, which send maintenance signals directly to the GSCs. GSCs are easily identified through histological staining against vasa protein (to identify germ cells) and 1B1 protein (to outline cell structures and a germline specific fusome structure). Their physical attachment to the cap cells is necessary for their maintenance and activity. A GSC will divide asymmetrically to produce one daughter cystoblast, which then undergoes 4 rounds of incomplete mitosis as it progresses down the ovariole (through the process of oogenesis) eventually emerging as a mature egg chamber; the fusome found in the GSCs functions in cyst formation and may regulate asymmetrical cell divisions of the GSCs. Because of the abundant genetic tools available for use in Drosophila melanogaster and the ease of detecting GSCs through histological stainings, researchers have uncovered several molecular pathways controlling GSC maintenance and activity.Ting, X., 2013. Control of germline stem cell self‐renewal and differentiation in the Drosophila ovary: concerted actions of niche signals and intrinsic factors. Wiley Interdisciplinary Reviews: Developmental Biology, 2(2), pp.261-273.Zhang, H. and Cai, Y., 2020. Signal transduction pathways regulating Drosophila ovarian germline stem cells. Current opinion in insect science, 37, pp.1-7.
Molecular mechanisms of GSC maintenance and activity
Local signals
The Bone Morphogenetic Protein (BMP) ligands Decapentaplegic (Dpp) and Glass-bottom-boat (Gbb) ligand are directly signalled to the GSCs, and are essential for GSC maintenance and self-renewal. BMP signalling in the niche functions to directly repress expression of Bag-of-marbles (Bam) in GSCs, which is up-regulated in developing cystoblast cells. Loss of function of dpp in the niche results in de-repression of Bam in GSCs, resulting in rapid differentiation of the GSCs. Along with BMP signalling, cap cells also signal other molecules to GSCs: Yb and Piwi. Both of these molecules are required non-autonomously to the GSCs for proliferation-piwi is also required autonomously in the GSCs for proliferation. In the germarium, BMP signaling has a short-range effect, therefore the physical attachment of GSCs to cap cells is important for maintenance and activity.
Physical attachment of GSCs to cap cells The GSCs are physically attached to the cap cells by Drosophila E-cadherin (DE-cadherin) adherens junctions and if this physical attachment is lost GSCs will differentiate and lose their identity as a stem cell. The gene encoding DE-cadherin, shotgun (shg), and a gene encoding Beta-catenin ortholog, armadillo, control this physical attachment. A GTPase molecule, rab11, is involved in cell trafficking of DE-cadherins. Knocking out rab11 in GSCs results in detachment of GSCs from the cap cells and premature differentiation of GSCs. Additionally, zero population growth (zpg), encoding a germline-specific gap junction is required for germ cell differentiation.
Systemic signals regulating GSCs Both diet and insulin-like signaling directly control GSC proliferation in Drosophila melanogaster. Increasing levels of Drosophila insulin-like peptide (DILP) through diet results in increased GSC proliferation. Up-regulation of DILPs in aged GSCs and their niche results in increased maintenance and proliferation. It has also been shown that DILPs regulate cap cell quantities and regulate the physical attachment of GSCs to cap cells.
Renewal mechanisms There are two possible mechanisms for stem cell renewal, symmetrical GSC division or de-differentiation of cystoblasts. Normally, GSCs will divide asymmetrically to produce one daughter cystoblast, but it has been proposed that symmetrical division could result in the two daughter cells remaining GSCs. If GSCs are ablated to create an empty niche and the cap cells are still present and sending maintenance signals, differentiated cystoblasts can be recruited to the niche and de-differentiate into functional GSCs.
Stem cell aging As the Drosophila female ages, the stem cell niche undergoes age-dependent loss of GSC presence and activity. These losses are thought to be caused in part by degradation of the important signaling factors from the niche that maintains GSCs and their activity. Progressive decline in GSC activity contributes to the observed reduction in fecundity of Drosophila melanogaster at old age; this decline in GSC activity can be partially attributed to a reduction of signaling pathway activity in the GSC niche. It has been found that there is a reduction in Dpp and Gbb signaling through aging. In addition to a reduction in niche signaling pathway activity, GSCs age cell-autonomously. In addition to studying the decline of signals coming from the niche, GSCs age intrinsically; there is age-dependent reduction of adhesion of GSCs to the cap cells and there is accumulation of reactive oxygen species (ROS) resulting in cellular damage which contributes to GSC aging. There is an observed reduction in the number of cap cells and the physical attachment of GSCs to cap cells through aging. Shg is expressed at significantly lower levels in an old GSC niche in comparison to a young one.
GSC niche in Drosophila testes Males of Drosophila melanogaster each have two testes – long, tubular, coiled structures – and at the anterior most tip of each lies the GSC niche. The testis GSC niche is built around a population of non-mitotic hub cells (a.k.a. niche cells), to which two populations of stem cells adhere: the GSCs and the somatic stem cells (SSCs, a.k.a. somatic cyst stem cells/cyst stem cells). Each GSC is enclosed by a pair of SSCs, though each stem cell type is still in contact with the hub cells. In this way, the stem cell niche consists of these three cell types, as not only do the hub cells regulate GSC and SSC behaviour, but the stem cells also regulate the activity of each other. The Drosophila testis GSC niche has proven a valuable model system for examining a wide range of cellular processes and signalling pathways.