Hematopoietic stem cells ( HSCs ) are stem cells that give rise to other blood cells. This process is called hematopoiesis. [1] In vertebrates, already definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the (midgestational) aorta-gonadal-mesonephros region, through a process known as endothelial-to-hematopoietic transition. [2] [3] In adults, hematopoiesis occurs in the red bone marrow, the core of most bones. embryo called red bone marrow mesoderm comes from the layer of.
| Overview of normal human hematopoiesis | |
| description | |
|---|---|
| system | hematopoietic system |
| place | bone marrow |
| Celebration | stem cells that give rise to other blood cells |
| identifier | |
| Latin | cellula hematopoietica precursoria |
| Acronyms) | hsc |
| Net | D006412 |
| th | H2.00.01.0.00006 |
| anatomical terms of microscopic anatomy |
Hematopoiesis is the process by which all mature blood cells are produced. This must balance the enormous production requirements (the average person produces more than 500 billion blood cells each day) with the need to regulate the number of each blood cell type in circulation. In vertebrates, the vast majority of hematopoiesis occurs in the bone marrow and is derived from a limited number of hematopoietic stem cells that are capable of multipotentiality and extensive self-renewal.
Hematopoietic stem cells give rise to different types of blood cells, called myeloid and lymphoid. Both myeloid and lymphoid lineages are involved in dendritic cell formation. Myeloid cells include monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, and megakaryocytes to platelets. Lymphoid cells include T cells, B cells, natural killer cells, and innate lymphoid cells., The definition of hematopoietic stem cells has evolved since HSCs were first discovered in 1961 [4] Hematopoietic tissue includes cells with long- and short-term regeneration potential and committed multipotent, oligopotent, and unipotent progenitors. Hematopoietic stem cells make up 1:10,000 cells in myeloid tissue.
HSC transplants are used in the treatment of cancer and other immune system disorders.
structure
They are round, non-adherent, with a round nucleus and a low cytoplasm-to-nucleus ratio. In shape, hematopoietic stem cells are similar to lymphocytes.
place
During (mouse and human) embryonic development the earliest hematopoietic stem cells are found in the aorta-gonad-mesonephros region and the vitelline and umbilical arteries. [6] [7] [8] A little later, HSCs are also found in the placenta, yolk sac, fetal head, and fetal liver. [2] [9]
Hematopoietic stem cells are found in the bone marrow of adults, particularly in the pelvis, femur, and sternum. They are also found in cord blood and, to a lesser extent, in peripheral blood. [10]
Stem and progenitor cells can be taken from the pelvis, at the iliac crest, using a needle and syringe. [11] The cells may be removed as fluid (to perform a smear to view cell morphology) or they may be removed via a core biopsy (the architecture or relationship of the cells to each other and the bone). to maintain).
subtype
Colony-forming units are a subtype of HSC. (This meaning of the term is different from the colony-forming units of microbes, which is a cell counting unit.) There are different types of HSC colony-forming units:
- Colony Forming Unit – Granulocyte – Erythrocyte – Monocyte – Megakaryocyte ( CFU – GEMM )
- Colony Forming Unit – Lymphocyte ( CFU-L )
- Colony Forming Unit – Erythrocyte ( CFU-E )
- Colony Forming Unit – Granulocyte – Macrophage ( CFU – GM )
- Colony Forming Unit – Megakaryocyte (CFU-Meg)
- Colony Forming Unit- Basophil (CFU-B)
- Colony Forming Unit-Eosinophil (CFU-Eos)
The above CFUs are based on lineage. Another CFU, colony-forming unit-spleen (CFU-S), was the basis for clonal colony formation in vivo, which relies on the ability of infected bone marrow cells to give rise to clones of mature hematopoietic cells in the spleen. . Irradiated mice after 8 to 12 days. It was widely used in early studies but is now considered to measure more mature progenitor or transit-amplifying cells rather than stem cells [ citation needed ].
stem cell isolation
Since hematopoietic stem cells cannot be isolated as a pure population, it is not possible to identify them under a microscope. [ citation needed ]Hematopoietic stem cells can be identified or isolated using flow cytometry where a combination of several different cell surface markers (particularly CD34) are used to differentiate rare hematopoietic stem cells from surrounding blood cells. goes. Hematopoietic stem cells lack expression of mature blood cell markers and are thus termed in-. The lack of expression of lineage markers is used in combination with the detection of several positive cell-surface markers to differentiate hematopoietic stem cells. In addition, hematopoietic stem cells are characterized by their small size and low staining with important dyes such as rhodamine 123 (rhodamine low ) or Hoechst 33342 (side population).
Celebration
hematopoiesis
Hematopoietic stem cells are essential for hematopoiesis, the formation of cells within the blood. Hematopoietic stem cells can replenish all types of blood cells (i.e., are multipotent) and can self-renew. A small number of hematopoietic stem cells can expand to generate very large numbers of daughter hematopoietic stem cells. This phenomenon is used in bone marrow transplantation, [12] when a small number of hematopoietic stem cells reconstitute the hematopoietic system. This process indicates that, after bone marrow transplantation, symmetric cell division into two daughter hematopoietic stem cells should occur.
Stem cell self-renewal occurs in the stem cell niche in the bone marrow, and it is reasonable to assume that key signals present in this niche would be important in self-renewal. [1] The environmental and molecular requirements for HSC self-renewal are of great interest, as understanding the ability of HSCs to replenish themselves will eventually allow the generation of expanded populations of HSCs in vitro that can be used therapeutically. can go.
passivity
Hematopoietic stem cells, like all adult stem cells, mostly exist in a state of quiescence, or reversible growth arrest. The altered metabolism of quiescent HCS allows cells to survive for extended periods in the hypoxic bone marrow environment. [13] When provoked by cell death or damage, hematopoietic stem cells exit the quiescence and begin to actively divide again. The transition from dormancy to proliferation and backward is controlled by the MEK/ERK pathway and the PI3K/AKT/mTOR pathway. [14] Uncontrolled transfusions can lead to stem cell exhaustion or the gradual loss of active hematopoietic stem cells in the blood system. [14]
Mobility
Hematopoietic stem cells have a greater ability than other immature blood cells to cross the bone-marrow barrier, and thus, can travel in the blood from the bone marrow to another bone in one bone. If they settle in the thymus, they can develop into T cells. In the case of embryonal and other extramedullary hematopoiesis. Hematopoietic stem cells can also settle and develop in the liver or spleen.
This enables hematopoietic stem cells to be harvested directly from the blood.
DNA damage with aging
DNA strand breaks in long-term hematopoietic stem cells occur during aging. [15] This accumulation is associated with a widespread attenuation of DNA repair and response pathways that depend on HSC quiescence. [15] Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as “non-homologous” because the break ends are ligated directly without the need for a homologous template. The NHEJ pathway depends on several proteins, including ligase 4, DNA polymerase Mu and NHEJ factor 1 (NHEJ1, also known as Cernunnos or XLF).
DNA ligase 4 (Lig4) has a highly specific role in the repair of double-strand breaks by NHEJ. Lig4 deficiency in the mouse causes progressive loss of hematopoietic stem cells during aging. [16] In pluripotent stem cells, lig4 deficiency results in DNA double-strand breaks and increased apoptosis. [17]
In polymerase mu mutant mice, hematopoietic cell development is defective in several peripheral and bone marrow cell populations, with an approximately 40% reduction in bone marrow cell numbers involving multiple hematopoietic lineages. [18] The proliferative capacity of the hematopoietic progenitor cells is also reduced. These characteristics correlate with a reduced ability to repair double-strand breaks in hematopoietic tissue.
NHEJ factor 1 deficiency in mice leads to premature aging of hematopoietic stem cells, as indicated by several lines of evidence that prolonged remyelination is defective and worsens over time. [19] Using a human induced pluripotent stem cell model of NHEJ1 deficiency, it was shown that NHEJ1 has an important role in promoting the survival of primitive hematopoietic progenitors. [20] These NHEJ1-deficient cells have a weak NHEJ1-mediated repair capacity that is markedly unable to deal with DNA damage induced by physiological stress, normal metabolism, and ionizing radiation. [20]
The sensitivity of hematopoietic stem cells to Lig4, DNA polymerase Mu and NHEJ1 deficiency suggests that NHEJ is a major determinant of the ability of stem cells to maintain themselves against physiological stress over time. [16] Rossi et al. [21] found that endogenous DNA damage accumulates with age even in wild-type hematopoietic stem cells, and suggested that DNA damage accumulation may be an important physiological mechanism of stem cell aging.
clinical significance
transplant
Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood. [22] [23] [24] It can be autologous (the patient’s stem cells are used), allogeneic (the stem cells come from a donor), or syngeneic (from an identical twin). [22] [23]
This is often done for patients with certain cancers of the blood or bone marrow, such as multiple myeloma or leukemia. [23] In these cases, the recipient’s immune system is usually destroyed by radiation or chemotherapy before the transplant. Infection and graft versus host disease are major complications of allogeneic HSCT. [23]
To harvest stem cells from circulating peripheral blood, blood donors are injected with a cytokine, such as granulocyte-colony stimulating factor (G-CSF), which causes cells to leave the bone marrow and circulate in blood vessels. inspires. [25] In mammalian embryology, definitive hematopoietic stem cells are first detected in the AGM (aorta–gonad–mesonephros), and then extensively expanded in the fetal liver before colonizing the bone marrow before birth. [26]
Hematopoietic stem cell transplantation is a dangerous procedure with many potential complications; It is reserved for patients with life-threatening diseases. As survival after the procedure has increased, its use has expanded beyond cancer to autoimmune diseases [27] [28] and hereditary skeletal dysplasia; especially fatal infantile osteopetrosis [29 ] [30] and mucopolysaccharidosis. [31]
Research
behavior in culture
A cobblestone sphere-forming cell (CAFC) assay is a cell culture-based empirical assay. When plated on a confluent culture of the stromal feeder layer, a fraction of the hematopoietic stem cells creep between the gaps (even though the stromal cells are touching each other) and eventually adhere to the stromal cells and the substrate (here the surface of the dish). ) settle or get trapped between. In cellular processes between stromal cells. Emperipolesis is the in vivo phenomenon in which one cell is completely engulfed by another (eg thymocytes in thymic nurse cells); On the other hand, when in vitro, lymphoid lineage cells crawl under nurse-like cells, the process is referred to as pseudoemperipolesis. A similar phenomenon is observed in the HSC field in cell culture terminology. Cobblestones are more commonly known by area-forming cells (CFCs), meaning that areas or groups of cells appear dull cobblestone-like under phase contrast microscopy compared to other hematopoietic stem cells. , which are refractive. This is because cells floating loosely on top of stromal cells are spherical and thus refractive. However, crawling cells beneath the stromal cells are flattened and thus, not refractive. The mechanism of Pseudoemperipolis is only recently coming to light. This may be mediated by interactions through CXC chemokines (eg, SDF1) and the receptor for α4β1 integrin, CXCR4 (CD184). [32]
repopulation kinetics
Hematopoietic stem cells (HSC) cannot be easily observed directly, and therefore, their behavior needs to be predicted indirectly. Clonal studies are likely to be the closest technique to single-cell in vivo studies of HSCs. Here, sophisticated experimental and statistical methods are used to ascertain that, with a high probability, a single HSC is engrafted in a transplant administered to a lethally irradiated host. Clonal expansion of this stem cell can be observed over time by monitoring the percentage of donor-type cells in the blood as the host is reconstituted. The resulting time series is defined as the recombination kinetics of HSCs.
The reconstitution kinetics are very heterogeneous. However, using symbolic dynamics, one can show that they fall into a finite number of classes. [33] To prove this, several hundred experimental recombination kinetics from clonal Thy-1 lo Sca-1 + Lin – c-Kit + HSCs were shown in symbolic sequences by assigning “+”, “-“, and “~” symbols. was translated. Two serial measurements of percent donor-type cells have a positive, negative, or unchanged slope, respectively. Using the Hamming distance, the recombination patterns were subjected to cluster analysis yielding 16 distinct groups of kinetics. To conclude the empirical proof, the Laplace add-one approach [ clarification needed ]] was used to determine that the probability of finding kinetics involved in these 16 clusters is very low. By corollary, this result suggests that the hematopoietic stem cell compartment is also heterogeneous by dynamical criteria.
Originally it was believed that all hematopoietic stem cells were similar in their self-renewal and differentiation abilities. This view was challenged by the 2002 discovery by the Müller-Sieburg group in San Diego, which illustrated that different stem cells can show distinct repopulation patterns that are epigenetically predetermined intrinsic properties of the clonal Thy-1 Low Sca-1 + Lin – G Kit + HSC. [34] [35] [36] The results of these clonal studies led to the notion of lineage bias. Using the ratio of lymphoid (L) to myeloid (M) cells in the blood as a quantitative marker, the stem cell compartment can be divided into three categories of HSCs.
Subsequently, other groups confirmed and shed light on the original findings. [37] For example, Eve’s group confirmed in 2007 that re-population dynamics, long-term self-renewal capacity, and My-bi and Ly-bi are stably inherited intrinsic HSC properties. [38] In 2010, Goodell’s group provided additional insights regarding the molecular basis of lineage bias in the side population (SP) SCA-1 + Lin – c-Kit + HSCs. [39] As previously shown for IL-7 signaling, it was found that My-bi and Ly-bi, a member of the transforming growth factor family (TGF-beta), induce and inhibit HSC proliferation, respectively.
Word – medium
From Greek hematoma-, combining form haima “blood”, and from the Latin form of Greek porticos “capable of, creative, productive”, from poiein “to create, create”.
