Diagram of cells that arise from<unk> s during the process of hematopoiesis. Haematopoiesis<unk> s are essential to haematopoiesis, the formation of the cells within blood.<unk> s can replenish all blood cell types (i.e., are multipotent) and self-renew. A small number of<unk> s can expand to generate a very large number of daughter<unk> s. This phenomenon is used in bone marrow transplantation, when a small number of<unk> s reconstitute the<unk>  system. This process indicates that, subsequent to bone marrow transplantation, symmetrical cell divisions into two daughter<unk> s must occur.<unk>  cell self-renewal is thought to occur in the<unk>  cell niche in the bone marrow, and it is reasonable to assume that key signals present in this niche will be important in self-renewal. There is much interest in the environmental and molecular requirements for<unk>  self-renewal, as understanding the ability of<unk>  to replenish themselves will eventually allow the generation of expanded populations of<unk>  in vitro that can be used therapeutically. Quiescence<unk> s, like all adult<unk>  cells, mostly exist in a state of quiescence, or reversible growth arrest. The altered metabolism of quiescent<unk> s helps the cells survive for extended periods of time in the hypoxic bone marrow environment. When provoked by cell death or damage,<unk> s exit quiescence and begin actively dividing again. The transition from dormancy to propagation and back is regulated by the MEK/ERK pathway and PI3K/AKT/mTOR pathway. Dysregulation of these transitions can lead to<unk>  cell exhaustion, or the gradual loss of active<unk> s in the blood system. Mobility<unk> s have a higher potential than other immature blood cells to pass the bone marrow barrier, and, thus, may travel in the blood from the bone marrow in one bone to another bone. If they settle in the thymus, they may develop into T cells. In the case of fetuses and other extramedullary hematopoiesis.<unk> s may also settle in the liver or spleen and develop. This enables<unk> s to be harvested directly from the blood. DNA damage with aging DNA strand breaks accumulate in long term<unk> s during aging. This accumulation is associated with a broad attenuation of DNA repair and response pathways that depends on<unk>  quiescence. 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 directly ligated 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 a progressive loss of<unk> s during aging. Deficiency of lig4 in pluripotent<unk>  cells results in accumulation of DNA double-strand breaks and enhanced apoptosis. In polymerase mu mutant mice,<unk>  cell development is defective in several peripheral and bone marrow cell populations with about a 40% decrease in bone marrow cell number that includes several<unk>  lineages. Expansion potential of<unk>  progenitor cells is also reduced. These characteristics correlate with reduced ability to repair double-strand breaks in<unk>  tissue. Deficiency of NHEJ factor 1 in mice leads to premature aging of<unk> s as indicated by several lines of evidence including evidence that long-term repopulation is defective and worsens over time. Using a human induced pluripotent<unk>  cell model of NHEJ1 deficiency, it was shown that NHEJ1 has an important role in promoting survival of the primitive<unk>  progenitors. These NHEJ1 deficient cells possess a weak NHEJ1-mediated repair capacity that is apparently incapable of coping with DNA damages induced by physiological stress, normal metabolism, and ionizing radiation. The sensitivity of<unk> s to Lig4, DNA polymerase mu and NHEJ1 deficiency suggests that NHEJ is a key determinant of the ability of<unk>  cells to maintain themselves against physiological stress over time. Rossi et al. found that endogenous DNA damage accumulates with age even in wild type<unk> s, and suggested that DNA damage accrual may be an important physiological mechanism of<unk>  cell aging.
Hematopoietic stem cell
Lymphoblast
Stem cell
Progenitor cell
Megakaryocyte–erythroid progenitor cell
Thymocyte
Monocyte
Dendritic cell