HSC niche refers to a highly specialized and unique microenvironment that provides hematopoietic stem cells (HSCs) with all the signals necessary to regulate their survival, proliferation, and differentiation. These niches are specifically designed to be suitable for particular stages of hematopoiesis and are composed of plastic and adaptable supporting cells that can dynamically respond to external signals and adjust to changing physiological conditions.
Among the various stromal cells for the HSC niche, MSCs take the lead
Many different cells participate and contribute to the formation of a very special, stable, and safe nurturing space or “nest” for HSCs—the niche environment. As mentioned earlier, the cells surrounding parenchymal cells and providing structural support and guidance are called stromal cells, and the HSC niche also contains numerous stromal cells that support the parenchymal HSCs. These include osteoblasts of the bone endosteum, pericytes around blood vessels, bone marrow adipocytes, reticular cells, and MSC-like stromal cells such as CAR cells and LepR⁺ stromal cells.
They anchor HSCs through adhesive proteins and secrete chemokine proteins like CXCL12 and SCF to maintain HSC dormancy, promote self-renewal, inhibit differentiation, and secrete anti-inflammatory cytokines (such as IL-10) to protect HSCs from excessive stress or immune attack, thereby creating a specialized protective space for them. The role of MSCs in regulating HSC survival, dormancy, regeneration, and differentiation within the niche vividly demonstrates the identity of MSCs as stromal rather than stem cells.
Long-term / Short-term (LT/ST) HSCs
To maintain hematopoietic homeostasis throughout life, the self-renewal ability of HSCs must be very tightly regulated. In this regard, HSCs can be subdivided into long-term (LT) and short-term (ST) HSCs. LT-HSCs possess strong regenerative capacity and can persist for years to an entire lifetime, whereas ST-HSCs have a relatively short lifespan of several weeks to months and a limited regenerative potential. They can be distinguished by the markers expressed on their cell surface. These two types may be compared to an “original copy” carefully preserved for long-term use and a “duplicate” that can be immediately used when needed.
According to a study that measured telomere length shortening during cell division to estimate how many times LT-HSCs divide over a lifetime for self-renewal, they undergo about 56 divisions in total. [1] After reaching adulthood, their division frequency slows to approximately once every four years. LT-HSCs remain in a dormant state (G0 phase) with cell cycle arrest to preserve their self-renewal capacity and divide only under special circumstances such as depletion or damage of progenitor pools or infection. The daily production of hundreds of billions of blood cells is carried out not by LT-HSCs but by ST-HSCs and their downstream progenitors such as multipotent progenitors (MPPs) and lineage-committed progenitors that have already differentiated from HSCs.
HSC niche
HSCs can be classified not only by their regenerative capacity and division frequency (LT/ST) but also by their spatial localization. Traditionally, the specific residence space (niche) for HSCs in the bone marrow is divided into the endosteal niche (near the bone) and the vascular niche (toward the marrow center). The endosteal niche near the bone surface is considered a storage site for long-term HSCs, while the vascular niche serves as an active zone for HSC proliferation and differentiation to ensure the continuous supply of blood cells. As described earlier, the sinusoidal capillaries—with discontinuous walls that allow free molecular movement—constitute the structural form of this vascular niche. These sinusoids serve as the exit routes through which differentiated blood cells enter circulation. LT-HSCs and ST-HSCs tend to localize preferentially in the endosteal and vascular regions, respectively, consistent with their functional characteristics.
Endosteal (Endosteum) Niche
Within the bone marrow, the area close to the endosteum contains many small arterioles, where the vascular network is relatively underdeveloped and oxygen supply is limited. Consequently, mitochondrial energy metabolism using oxygen is less active, allowing reactive oxygen species (ROS) levels to remain low. Dormant HSCs intentionally maintain a low metabolic rate, thereby generating less ROS to minimize DNA damage and premature aging. [2] In contrast, the vascular niche around sinusoids in the central marrow is relatively oxygen-rich, metabolically active, and thus has higher ROS levels. This high-ROS environment can act as a signal that activates HSCs for proliferation and differentiation.
In essence, the endosteal niche serves as a dedicated space to minimize DNA damage and prevent the decline of regenerative potential that could occur with repeated divisions during hematopoietic regeneration. What allows HSCs to remain in this area is that osteoblasts of the endosteum express adhesion molecules such as N-cadherin and VCAM-1, and produce the bone matrix protein osteopontin to physically anchor HSCs. Osteoblasts also secrete signaling molecules such as CXCL12, SCF, thrombopoietin (TPO), and Angiopoietin-1, which help HSCs survive and stay in the quiescent G₀ phase. For this reason, the endosteal niche is sometimes referred to as the osteoblastic niche.
However, other factors also contribute to maintaining dormancy. MSCs near the endosteum secrete SCF and CXCL12, while the hypoxic environment caused by low blood flow induces the expression of the transcription factor HIF-1α, which plays an important role in establishing the endosteal niche environment. NG2⁺ pericytes surrounding the arterioles near the endosteum also secrete SCF and CXCL12, helping HSCs remain in a deeply dormant state. Meanwhile, sympathetic nervous hormones such as norepinephrine regulate HSC quiescence by suppressing CXCL12 expression.
Vascular Niche
Unlike the long-term storage of HSCs in the endosteal niche, the vascular niche is the area where HSC proliferation and differentiation occur more actively to replenish blood cells. Consequently, more progenitor cells derived from HSCs are found here, supported by diverse stromal cells. Among them, pericytes surrounding the blood vessels play a central role and exhibit characteristics similar to MSCs. Pericytes share surface markers with MSCs and can differentiate into osteocytes, chondrocytes, and adipocytes. Because of these shared properties and their role as stromal supporters of stem cells, they are often called “MSC-like cells attached to the vascular wall.” Due to this ability, pericytes have gained increasing attention as potential therapeutic targets and are being actively studied for clinical applications.
Various stromal cells exist within the vascular niche. Notably, CAR cells and LepR⁺ stromal cells are MSC-like stromal cells that serve as central components. CAR (CXCL12-abundant reticular) cells, as the name suggests, secrete large amounts of the chemokine CXCL12, while LepR⁺ stromal cells express the leptin receptor (LepR). Although both are located in the vascular niche, they secrete CXCL12 and SCF, which play essential roles in regulating the dormancy of LT-HSCs residing in the endosteal niche. This overlap indicates that, unlike the previously held dichotomous view, the boundaries and functions between the two niches are now understood to be more fluid and interrelated.
Essential niche factors
Now, let us briefly provide additional explanations about the substances associated with the HSC niche, known as niche factors.
NG2 (Neuron-glial antigen 2, CSPG4)
This is a cell surface proteoglycan and one of the representative markers found in perivascular cells surrounding the endothelial cells of small arterioles located near the endosteum. An NG2⁺ pericyte refers to a perivascular cell that expresses NG2, which secretes factors such as SCF and CXCL12 in a specific pattern to maintain HSCs in a quiescent state.
VCAM-1 (Vascular Cell Adhesion Molecule-1)
Along with adhesion molecules such as N-cadherin, VCAM-1 binds to VLA-4 (α4β1 integrin) on HSCs, firmly anchoring them in place to prevent them from entering circulation. Osteopontin and fibronectin—extracellular matrix (ECM) adhesion proteins secreted by osteoblasts—also bind to the same α4β1 integrin receptors on HSCs. Thus, the α4β1 (VLA-4) integrin is a key receptor responsible for HSC anchoring and homing back into the endosteal niche.
CXCL12 (Stromal Cell-Derived Factor-1, SDF-1)
CXCL12, also called SDF-1, is a chemokine that binds to CXCR4 (or CXCR7) receptors on HSCs and progenitor cells, acting as a chemoattractant that guides them to specific sites. MSCs secrete large amounts of CXCL12 to recruit HSCs into the niche, where they remain quiescent. Some HSCs circulate in the blood, and CXCL12 also mediates their homing back to the niche. Additionally, platelet granules released during hemostasis contain CXCL12, which helps stabilize platelet plugs and recruits endothelial progenitor cells and HSCs to damaged vessels for repair.
SCF (Stem Cell Factor)
Binds to the c-Kit receptor on HSCs to activate intracellular signaling, preventing apoptosis, maintaining metabolic activity, and preserving long-term self-renewal. When SCF signaling weakens, HSCs shift from dormancy toward differentiation.
Angiopoietin-1 (Ang-1)
A pro-angiogenic protein that binds to the Tie2 receptor on HSCs, anchoring them firmly in the endosteal niche and inducing cell-cycle inhibitor genes to maintain dormancy.
TGF-β (Transforming Growth Factor-beta)
Promotes the expression of cell-cycle inhibitory genes in HSCs, preventing excessive proliferation and preserving long-term regenerative potential. When this signal weakens, HSCs become more active and differentiate into progenitor cells.
LepR⁺ (Leptin receptor-positive) stromal cells
These are stromal cells expressing leptin receptors in the bone marrow and are located around blood vessels. They are MSC-like stromal cells, and like CAR cells, they secrete CXCL12 and SCF to support the self-renewal and survival of HSCs. Considering that leptin is a hormone secreted by adipocytes, it can be inferred that these cells possess the potential to differentiate into adipocytes later on.
MSC-like vascular stromal cells: Pericytes
Examining the structure of blood vessels, the inner wall in direct contact with the blood is composed of endothelial cells. In large blood vessels, these endothelial cells are surrounded by several layers of vascular smooth muscle cells (VSMCs), which contract and relax to regulate blood flow and blood pressure. However, in smaller vessels such as capillaries or arterioles, there are no such smooth muscle layers; instead, pericytes that wrap around the vessel wall locally and finely control microcirculation.
The term pericyte literally means “cells around the vessel,” and these cells are essential components located around small blood vessels, extending finger-like processes to encase endothelial cells. They are found in most tissues of the body, although their ratio to endothelial cells varies among organs—for example, about 1:1000 in skeletal muscle, whereas in the central nervous system or retina, the ratio can range from 1:3 to as high as 1:1. [3] Pericytes can be regarded as reliable supporting cells for endothelial cells, communicating with them through direct physical contact or by secreting various paracrine factors.
Looking into their functions, pericytes maintain the structural stability of vessel walls and prevent vascular leakage through direct contact with endothelial cells. They inhibit excessive proliferation or migration of endothelial cells and also participate in the formation of new blood vessels when required. Under normal conditions, pericytes remain attached to endothelial cells to maintain vascular stability and homeostasis. However, when angiogenesis is needed, pericytes respond to vascular growth signals such as VEGF, angiopoietin-2 (ANG-2), and chemokines by detaching from endothelial cells, thereby enabling new vessel formation. Once new vessels are formed, pericytes are attracted back by platelet-derived growth factor (PDGF-β) secreted from endothelial cells, re-encase the vessels, and stabilize the vessel walls during maturation.
Pericytes also secrete various signaling molecules that promote strong tight-junction formation between endothelial cells, preventing leakage. In particular, capillaries in the brain and central nervous system have a high proportion of pericytes, forming an even more compact and robust barrier that blocks toxins while selectively transporting nutrients to protect neurons. Loss of pericytes leads to disruption of the blood–brain barrier, resulting in edema, neuroinflammation, and neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease.
Perhaps the most fascinating feature of pericytes is their ability to differentiate into various cell types. They share similar surface markers with MSCs derived from the mesoderm and can respond to factors secreted by endothelial cells to differentiate along the classic MSC lineages—osteocytes, chondrocytes, and adipocytes. They can also differentiate into smooth muscle cells to reconstruct vascular walls or behave like fibroblasts by secreting extracellular matrix (ECM) components to regenerate tissue.
In other words, this multipotent differentiation ability allows pericytes to contribute to tissue regeneration in cases of injury or disease. Pericytes residing in skeletal muscle contribute to muscle fiber regeneration, while those in the heart and vascular system participate in vascular smooth muscle formation. Because of these properties, pericytes are considered either highly similar to or essentially the same as MSCs. With respect to tissue regeneration, pericytes also possess immunomodulatory abilities similar to those of MSCs. Several studies have also shown that pericytes can differentiate into immune cells such as dendritic cells and macrophages, thereby playing a role in mediating inflammatory responses.
The role of pericytes in HSC niches
In the context of HSCs, the key point to note is the role of pericytes in the two distinct niches of HSCs. Pericytes surrounding arterioles in the endosteal niche express NG2 and help maintain HSCs in a quiescent state, whereas pericytes in the vascular niche contribute more actively to the activation, differentiation, and circulation of HSCs.
The effect of co-transplantation of HSCs and MSCs
The influence of MSCs on HSC survival is also evident in transplantation studies. According to research investigating the feasibility and safety of co-transplanting HSCs with MSCs, numerous animal experiments have demonstrated that co-transplantation promotes HSC engraftment and prevents transplant failure. When MSCs derived from bone marrow or adipose tissue are transplanted together with HSCs, the composition of both long-term and short-term HSCs is significantly enhanced.
This strategy is particularly valuable when the HSC niche itself is impaired by disease and cannot adequately support HSC transplantation. Co-transplantation with MSCs is thus recognized as an effective method to rapidly restore hematopoietic activity after transplantation and to reduce the risk of transplant failure.
[References]
[1] Predicting the number of lifetime divisions for hematopoietic stem cells from telomere length measurements
doi: 10.1016/j.isci.2023.107053
[2] Dissecting the bone marrow HSC niches
https://doi.org/10.1038/cr.2016.71
[3] Concise Review: The Regenerative Journey of Pericytes Toward Clinical Translation
doi: 10.1002/stem.2846
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