Hematopoietic stem cell (HSC) niches provide an essential microenvironment for long-term replenishment of mature cells that are lost due to normal tissue loss or drastic circumstances. In a steady-state environment, the total number of HSCs remains consistent as the HSCs oscillate between quiescence, proliferation, self-renewal, and differentiation as a reaction to signals from their microenvironment order to replace mature cells. In response to stress or injury, the HSCs niche will fluctuate to meet the demands of the organism and strive to maintain a state of homeostasis. The HSC niche is a fundamental part of an intricate system of molecular relationships that guide life-long cellular generation. As an integral part of that process, stem cell factor (SCF) is shown to promote HSC proliferation and adhesion and to promote the HSCs unique ability to engage in a migration and homing practice that supports homeostasis.
In perusing through the many avenues of stem cell research, a stem cell niche is the locale of a group of cells that allow a stem cell to maintain its identity by forming a functional and anatomical microenvironment that promotes the stem cell to maintain quiescence. Key properties of stem cells such as their regeneration and proliferation can be controlled by this cellular environment where the stem cells receive signals from the periphery that will trigger appropriate stem cell behavior regarding their progeny. The best models of a niche perpetuate that stem cells receive signals from a specific molecular pathway or a cell/adhesion molecule that will allow the niche cells a mechanism to regulate the stem cells and typically without this ability, stem cells will leave their niche and either divide, differentiate or apoptosis (Agosto, Mikola, & Hartenstein, 3048). The stem cell niche allows for homeostasis to be maintained by controlling the stem cells' self-renewal and progeny production in vivo by signaling stem cells to either differentiate or self-replicate (Purton & Scadden, 2). The stem cell niche, therefore, plays an important role in the regulation of homeostasis of stem cells that replenish mature cells that are constantly lost due to normal tissue turnover or injury maintaining a necessary balance for healthy cell renewal levels.
Hematopoietic stem cells (HSCs) primarily are located in the bone marrow (BM) even though they have been shown to circulate and reside in multiple tissues. The main focus has been to examine the endosteal and perivascular niches located in the BM as host environments for HSC niches, each providing different cellular contexts for an HSC function (Ugarte & Forsberg, 2535) HSCs are located at the endosteal lining of the BM cavities where specialized spindle-shaped N-cadherin osteoblasts (SNO) interact with a homotypic N-cadherin acting as an anchor for HSCs (Wilson & Murphy, 2748). The endosteal niche is located in a layer at the interface between the bone and the marrow and periosteum and contains several different cell types from the osteoblasts lineage including osteoprogenitor cells, osteoblasts, and osteocytes (Purton & Scadden, 4). Some studies have shown that HSCs can remain quiescent in an osteoblast-containing niche due to at least three molecules (N-cadherin, angiopoietin-1 and thrombopoietin) that regulate HSC quiescent by interactions with their receptors (N-cadherin, Tie-2 or Mpl, respectively) (Purton & Scadden 5). The perivascular niche is considered to encourage a more activated state for HSCs (Purton & Scadden 5). Located in the perivascular zone are endothelial cells that line all blood vessels in the body. However in the BM, they form a threshold between the hematopoietic cells and the blood (Purton & Scadden, 4). To enter the circulation, stem cells must migrate through a vascular barrier composed of endothelial cells, a basement membrane and a layer of adventitial cells (Pusic & DiPersio, 1950). In a study that discovered the SLAM antigens marking HSCs, it was shown that the majority of HSCs were in the perivascular region with only a minority (~16%) located at the periendosteal region supporting the theory of perivascular regions serving as a niche (Purton & Scadden, 4). A prevalent and related idea is that the HSCs are housed in the endosteal niche where quiescence is maintained and then they migrate to the perivascular niche to proliferate and differentiate (Frenette, 2). The idea is HSCs benefit from the more nutrient-rich microenvironment due to the saturated oxygen and growth factors that aid the generation of mature blood cells that will eventually be released into the peripheral circulation (Yin & Li, 1197). But defining the exact relationship has been difficult due to technical encumbrances ranging from preparation of BM sections, cell-specific labeling, and high-resolution detection methods (Ugarte & Forsberg, 2535). A recent study by Nombela-Arrieta utilized laser scanning cytometry (LSC) and confocal imaging that allowed for a larger section of tissue and the description of the three-dimensional vascular architecture of the BM to be examined. The results were to illuminate a BM environment that was highly vascularized, particularly at the bone-proximal regions. They were also able to demonstrate the enrichment of HSCs by quantifying the location and distribution of hematopoietic cells in the perivascular area of the bone-proximal regions. This discovery implies that vascular and endosteal niches should not be viewed as two different components but they are a single complex cellular microenvironment composed of highly vascularized endosteal regions (Ugarte & Foresberg, 2536). These regions are necessary for HSC maintenance supporting either quiescence or proliferation depending on demand
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Stem cell factor (SCF) is a cytokine that acts on primitive multi-lineage hematopoietic cells and stimulates the mobilization of myeloid, erythroid and lymphoid progenitors (Pusic & DiPersio, 1955). It is expressed by fibroblasts and endothelial cells throughout the body and promotes proliferation, migration, survival, and differentiation of hematopoietic progenitors, melanocytes and germ cells (Lennartsson & Ronnstrand, 1620). SCF is an important hematopoietic growth factor that can be found in both a membrane-bound glycoprotein and an insoluble form that binds to its receptor, c-Kit, activating its intrinsic tyrosine kinase activity (Lennartsson & Ronnstrand, 1620). As a hematopoietic growth factor, SCF has a well-established potential to stimulate in vitro and in vivo hematopoietic proliferation and is a prime mechanism of “emergency” hematologic response to acute blood cell loss, inflammation, and infection (Lowry, Deacon, Whitefield, McGrath & Quesenberry, 666). “SCF is produced in non-transplantable bone marrow stromal cells, endothelial cells and a subset of perivascular cells” (leptin receptor-positive, LepR+ cells) (Frenette, 2). The total deprivation and absence of either SCF of c-Kit are lethal. Deficiencies of either lead to severe anemia as a result of inhibited red and white blood cell production. It can also result in hypopigmentation and sterility, which shows the importance of cell communication ( Roskoski, 1). The expression pattern of c-Kit and SCF during mouse embryogenesis suggests that they are involved in migration of cells of the hematopoietic, germ cell, and melanoblast lineages (Lennartsson & Ronnstrand, 1620). They are also involved in the differentiation and proliferation of these cells.
To determine SCF as a primary emergency mechanism for hematopoietic proliferation in response to injury, inflammation or infection, an experiment was conducted using unfractionated marrow and FU8 marrow. It was established that the five growth factors of CSF-1, G-CSF, GM-CSF, IL-1a and IL-3, all at a 1x concentration level, produced consistent numbers of high proliferative potential colony-forming cells (HPP-CFCs) and total colonies. SCF, by itself, produced few colonies and no HPP-CFC in these populations. It was then shown that a significant loss of colony-forming ability was a result of reduction of the five-factor combination concentrations by 1 log, but the addition of SCF at lx concentration significantly restored HPP-CFC and total colony-forming capacity (Lowry, Deacon, Whitefield, McGrath & Quesenberry, 663). Thus, it is shown that SCF alone was not a factor in creating colonies but also did not change colony numbers while the five-factor growth combination was at 1x concentration levels, simulating the maintenance of a homeostasis environment. However, when the five-factor combination was depleted, simulating a loss of capacity, SCF significantly restored colony-forming capacity (Lowry, Deacon, Whitefield, McGrath & Quesenberry, 664). In this case, SCF was a factor.
In another experiment, the intent was to define the role of SCF in acute erythroid expansion and in homing of progenitor cells with their nurturing microenvironment in the splenic or bone marrow niche. The experiment used “a neutralizing anti-c-Kit receptor monoclonal antibody, ACK2,2X.29 to determine if blocking the c-Kit receptor from binding to the SCF would impact recovery from acute hemolytic anemia”(Broudy, Lin, Priestly, Nocka & Wolf, 79). The results show that acute erythroid cell expansion was impaired dramatically in the spleen, but not in the marrow, when c-kit receptor function was interrupted. The lack of hematopoiesis in the spleen was due, at least in part, to failure of hematopoietic progenitor cells to lodge in the spleen. Demonstrating that hematopoietic progenitor cells exposed to a neutralizing anti-c-kit receptor monoclonal antibody failed to lodge normally in the marrow and in the spleen in vivo, suggesting that signaling via the c-kit receptor is required for these processes. This result also supports the conclusion that SCF and its c-Kit receptor play a pivotal role in the adhesion interactions between the hematopoietic cells and the stromal cells (Broudy, Lin, Priestly, Nocka & Wolf, 79).
In summation, the hematopoietic stem cell niche is the anatomical location that promotes and maintains an ideal environment for cell renewal. It is very complex and adaptive, reacting to extrinsic and intrinsic signals that can either result in maintaining stem cell quiescence or direct self-renewal and differentiation, in order to maintain homeostasis. The HSC niche thrives in both the endosteal and perivascular niches, which has been postulated to be complementary components of a possible universal niche located in the BM. As an integral part of the complex matrix, the stem cell factor protein has been shown to play a crucial role in the proliferation, adhesion, and migration of HSCs through the interactions with its c-Kit receptor.
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