We have examined mesenchymal stem/stromal cells (MSCs) in detail in the previous articles. Now, let us turn our attention to the hematopoietic stem cells, which are supported and protected by MSCs.
Hematopoietic Stem Cells (HSCs)
From this point onward, hematopoietic stem cells will be referred to simply as HSCs for convenience. HSCs, which can be considered as close relatives of MSCs, are also derived from the mesodermal lineage in terms of origin, and therefore can be viewed as a type of mesenchymal cell. However, they are treated as a distinct category of stem cells because their differentiation potential, direction, anatomical localization, and, most importantly, their physiological functions and roles are fundamentally different from those of MSCs.
HSCs are responsible for producing all of the body’s blood cells throughout a person’s lifetime. The term “hematopoiesis,” originating from the Greek word meaning “to make blood,” refers to the process through which HSCs generate fully mature blood cells capable of performing essential physiological functions such as oxygen transport, immune defense, and blood coagulation. This process is not a mechanical one—it dynamically regulates both the quantity and composition of produced cells in response to environmental needs such as bleeding, infection, or oxygen deficiency, thereby ensuring the continuous renewal and replacement of blood cells throughout life.
Composition of Blood
Blood consists of cellular and liquid components. The liquid portion, plasma, serves as the medium that carries the cellular components—red blood cells, white blood cells, and platelets—and accounts for more than half of the total blood volume. Plasma is approximately 90% water, with the remainder composed of proteins such as albumin, antibodies, and fibrinogen, along with electrolytes, nutrients, hormones, and metabolic waste products. These substances originate from the liver, digestive organs, and endocrine glands and are transported throughout the body via the plasma. By contrast, serum refers to the liquid portion of blood after fibrinogen and other clotting factors have been removed. While HSCs generate blood cells, plasma is produced separately through various physiological pathways.
There are many types of blood cells derived from HSCs. In fact, the hematopoietic system possesses one of the highest regenerative capacities in the human body, producing approximately one trillion (10¹²) blood cells every day in the bone marrow. [1] Even short-lived cells such as red blood cells, platelets, and neutrophils are produced at a rate of about 300 billion per day. [2] Remarkably, despite this tremendous production rate, most HSCs remain in a dormant state (quiescence) and divide only once every 175 to 350 days. Another study using different measurement methods estimated that an HSC divides only about 56 times over a lifetime. [3] Although the figures vary slightly, the key point is that HSCs rarely divide. Much like preserving a master batch of soy sauce for long-term use in traditional Korean households, HSCs are carefully conserved for lifelong use, while progenitor cells (daughter cells) continue to divide and generate vast numbers of mature blood cells to maintain homeostasis. Limiting the frequency of HSC division is crucial—it helps preserve their long-term self-renewal capacity, prevents depletion and aging, and minimizes potential DNA damage (such as telomere shortening) and mutations that could arise from frequent replication.
The diversity of blood cells produced by HSCs illustrates their vital role in sustaining life. The differentiation pathways of HSCs are broadly divided into the myeloid and lymphoid lineages. Why is this initial bifurcation into the myeloid and lymphoid systems so significant, and why do both lineages ultimately give rise to immune cells? The distinction likely arises from the evolutionary divergence between innate and adaptive immunity. Early in evolution, only the innate immune system existed; later, the adaptive immune system evolved, giving rise to the lymphoid lineage. Thus, the immune response became divided into two complementary arms: the innate immune system, which reacts rapidly and non-specifically to invading pathogens, and the adaptive immune system, which remembers previously encountered antigens and mounts a targeted, antigen-specific response upon re-exposure. This organization forms an efficient and stable defense mechanism. Interestingly, except for red blood cells (which carry oxygen and nutrients) and platelets (which mediate blood clotting), nearly all other blood cells are immune cells. The figure below illustrates how HSCs self-renew while differentiating into various types of blood cells.
Cell Division of HSCs: Symmetric Division (2 HSCs or 2 MPPs) vs. Asymmetric Division (HSC + MPP)
HSCs derived from fetal tissues are rarely found in the spleen and liver, but most reside in the bone marrow (the primary lymphoid organ). Their number is extremely small—approximately one in every 50,000 cells—and this number is very strictly regulated to remain constant. HSCs are one of the tissue-specific multipotent stem cells, and they also perform two types of cell division: asymmetric division and symmetric division. Simply put, this means whether they proliferate into two identical cells or into two different cells. When there is no infection or pathological stimulus and the organism is in a stable state, most HSCs remain in a dormant (quiescent) condition, and only a few undergo cell division. During such division, one daughter cell retains the self-renewal capacity of the HSC itself, while the other daughter cell loses this regenerative ability and becomes a progenitor cell capable of differentiating into various other cells (Multipotent Progenitors, MPP). Through this process, the overall HSC pool remains unchanged. The figure above illustrates this. However, when infection or tissue damage occurs, a single HSC can divide into two HSCs or into two progenitor cells. Depending on the cytokines and other factors secreted in response to specific conditions at the time, HSCs perform symmetric or asymmetric division as needed, and through this regulation, even a very small number of HSCs can sustain the entire hematopoietic system throughout a lifetime.
Changes in the Site of Blood Formation During Embryonic Development
The site of blood formation is the bone marrow within bones. However, during embryonic development, the location where blood is generated changes several times in a temporal sequence. At the earliest stage of embryogenesis, before organs are fully formed, the very first primitive red blood cells (primitive hematopoiesis) are produced in the yolk sac to temporarily supply oxygen. As development progresses and the fetal heart begins to beat, self-renewing HSCs first appear in a region called the AGM (aorta-gonad-mesonephros). Subsequently, during the mid-developmental stage, hematopoiesis shifts to the liver and spleen, and finally, in the late developmental stage, the process takes root in the bone marrow inside the bones, where it establishes a permanent residence and continues blood production throughout life. From birth until puberty, hematopoiesis occurs in the bone marrow of most bones, but in adulthood, hematopoietic activity remains only in certain bones.
Site of Blood Formation: Niche?
After the fetal stage, most hematopoiesis in the human body occurs within the bone marrow, where hematopoietic stem cells gather in special protected zones or microenvironments called niches. The term “niche” is widely familiar in marketing as referring to a “market segment,” which makes its meaning in the context of hematopoiesis somewhat confusing, so I looked it up. In ecology, the word “niche” refers to the combination of abiotic factors (such as climate, soil type, and topography) required for a species to survive and function, together with the interactions (predation, competition, parasitism, symbiosis, etc.) it has with other species within its community. [4] Therefore, the hematopoietic stem cell niche can be understood as encompassing both the essential conditions necessary for HSC survival and the interactions with surrounding cells.
In fact, the term “niche” is also used in expressions such as neural stem cell niche, intestinal stem cell niche, thymic niche, and cancer stem cell niche. In all of these cases, it refers to a special microenvironment dedicated to supporting the survival, proliferation, and differentiation of stem cells—essentially, a “nurturing space” designed exclusively for them. If HSCs are likened to seeds, then the niche can be compared to the soil in which those seeds grow. A healthy microenvironment is an essential factor that regulates the functional characteristics of HSCs, including proliferation, differentiation, homing, engraftment, migration, apoptosis, and the maintenance of stable hematopoiesis.
Two Niches of HSCs: Endosteal Niche and Vascular Niche
The primary locations where hematopoiesis occurs within the bone marrow are classified into two main types: the endosteal niche, located near osteoblasts along the bone’s inner surface, and the vascular niche, located more centrally within the marrow, farther from the bone. It is somewhat difficult to visualize such subdivision within the already tiny space of the bone marrow, but the reason for this distinction seems to be functional: HSCs in the endosteal niche are generally maintained in a dormant state, while those in the vascular niche near blood vessels are more actively proliferating and differentiating. However, many studies show that this division is not always clearly defined.
Nevertheless, it is important to examine the rationale for distinguishing these two niches, as well as the various factors that help maintain their respective environments. Considering the vital importance of blood and immunity for human survival, it is evident that HSCs must remain undamaged and preserved through continuous, lifelong production without depletion. In other words, the self-renewal ability of HSCs must be strictly regulated to maintain lifelong hematopoietic homeostasis. It is generally accepted that long-term self-renewing HSCs (LT-HSCs) are stored in “reservoirs” near the endosteal region, while short-term HSCs actively differentiate and proliferate near the central vascular niche, from which newly produced blood cells rapidly enter circulation throughout the body. Although many new findings and ongoing research continue to refine our understanding, the following discussion focuses on what is currently known about the hematopoietic environment. Before examining the specific factors that define the bone marrow niches, let us first understand the vasculature within the bone marrow.
Vasculature Within the Bone Marrow
The bone marrow is located inside bones. As described in previous discussions about bone structure, the outer region of bone consists of compact bone, while the inner region is composed of spongy bone (trabecular bone). Compact bone is densely packed with structural units called osteons, which are arranged in concentric layers. In the center of each osteon runs a vertical channel known as the Haversian canal, through which blood vessels and nerves pass to deliver oxygen and nutrients. Additionally, transverse Volkmann’s canals connect these vertical channels, forming a network that interlinks blood and nerve supply. The inner spongy bone, adjacent to the bone marrow, consists of irregularly arranged trabeculae—small, beam-like structures resembling breakwaters—with porous, sponge-like spaces filled by the bone marrow.
Bones are living tissues that require a constant blood supply for growth and metabolism. Although the bone marrow is small in size, its vascular network is densely developed to provide oxygen and nutrients. The nutrient artery—a specialized artery that enters the bone through small holes called nutrient foramina in the compact bone—supplies blood to the spongy bone and marrow. Once inside the bone, this artery branches into smaller arterioles and capillaries that circulate through the marrow cavity. These capillaries then connect with sinusoidal capillaries, merge into larger veins, and finally exit the bone through the nutrient foramen. Nerves enter the bone along the same route, and they tend to be concentrated in areas where metabolic activity is higher.
3 types of capillaries
Before proceeding further, it is important to briefly explain the types of capillaries found within the bone marrow, as these are closely related to the special environment (niche) in which HSCs reside. Capillaries generally adopt structural forms optimized for the functions of their respective tissues. As shown in the figure below, capillaries are classified into three types: continuous, fenestrated, and discontinuous. Continuous capillaries are formed by tightly connected endothelial cells with an uninterrupted basement membrane, resulting in very low permeability. These are found in tissues such as the brain, lungs, and muscles, where only very small molecules can selectively pass through.
Fenestrated capillaries have small pores or windows in their endothelial lining, providing higher permeability. They are found in endocrine glands, kidneys, and the villi of the small intestine, allowing for the rapid passage of larger molecules such as nutrients and hormones. Discontinuous (sinusoidal) capillaries, on the other hand, have large gaps between endothelial cells and an incomplete basement membrane, allowing the passage of whole cells and large molecules. Because of their high permeability and exchange capacity, they are found in the liver, bone marrow, and spleen, where the movement of large particles such as blood cells occurs.
In summary, tissues that require a highly selective barrier—such as the central nervous system—contain continuous capillaries; tissues that require filtration or hormone exchange—such as kidney glomeruli and endocrine glands—contain fenestrated capillaries; and tissues that handle macromolecule transport, such as the liver (for metabolism and detoxification), bone marrow (for releasing hematopoietic progenitors into circulation), and spleen (for filtering aged red blood cells), utilize discontinuous or sinusoidal capillaries.
When examining the vasculature of the bone marrow specifically, the small arterioles located near the surface of the spongy bone, close to the endosteal region, are narrow arteries with relatively thick walls. Their endothelial cells are tightly connected, forming continuous capillaries (the first type shown in the figure below) with low permeability, restricting the movement of blood cells and substances. In contrast, the vessels widely distributed in the central region of the bone marrow are sinusoidal capillaries, which allow the effective passage of large cells and molecules. Through these sinusoidal capillaries, newly formed blood cells produced by the active proliferation of HSC progenitors are released into the circulatory system.
[References]
[1] Hematopoiesis: A Human Perspective
DOI 10.1016/j.stem.2012.01.006
[2] Chapter 7 Biological Properties of HSC: Scientific Basis for HSCT
https://www.ncbi.nlm.nih.gov/books/NBK553952/
[3] Predicting the number of lifetime divisions for hematopoietic stem cells from telomere length measurements
doi: 10.1016/j.isci.2023.107053
[4] https://education.nationalgeographic.org/resource/niche/
https://www.britannica.com/science/niche-ecology
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