Hematopoietic stem cell

Hematopoietic stem cell transplantation (HSCT) is the transplantation of

It is most often performed for patients with certain cancers of the blood or bone marrow, such as multiple myeloma or leukemia.^[17] In these cases, the recipient's immune system is usually destroyed with radiation or chemotherapy before the transplantation. Infection and graft-versus-host disease are major complications of allogeneic HSCT.^[17]

In order to harvest stem cells from the circulating peripheral blood, blood donors are injected with a cytokine, such as granulocyte-colony stimulating factor (G-CSF), that induces cells to leave the bone marrow and circulate in the blood vessels.^[19] In mammalian embryology, the first definitive Hematopoietic stem cells are detected in the AGM (aorta-gonad-mesonephros), and then massively expanded in the fetal liver prior to colonising the bone marrow before birth.^[20]

Hematopoietic stem cell transplantation remains a dangerous procedure with many possible complications; it is reserved for patients with life-threatening diseases. As survival following the procedure has increased, its use has expanded beyond cancer to

Stem cells can be used to regenerate different types of tissues. HCT is an established as therapy for chronic myeloid leukemia, acute lymphatic leukemia, aplastic anemia, and hemoglobinopathies, in addition to acute myeloid leukemia and primary immune deficiencies. Hematopoietic system regeneration is typically achieved within 2-4 weeks post-chemo- or irradiation therapy and HCT. HSCs are being clinically tested for their use in non-hematopoietic tissue regeneration.[26]

Aging of hematopoietic stem cells

DNA damage

DNA strand breaks accumulate in long term hematopoietic stem cells during aging.^[27] This accumulation is associated with a broad attenuation of DNA repair and response pathways that depends on HSC quiescence.^[27] 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 hematopoietic stem cells during aging.^[28] Deficiency of lig4 in pluripotent stem cells results in accumulation of DNA double-strand breaks and enhanced apoptosis.^[29]

In polymerase mu mutant mice, hematopoietic 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 hematopoietic lineages.^[30] Expansion potential of hematopoietic progenitor cells is also reduced. These characteristics correlate with reduced ability to repair double-strand breaks in hematopoietic tissue.

Deficiency of NHEJ factor 1 in mice leads to premature aging of hematopoietic stem cells as indicated by several lines of evidence including evidence that long-term repopulation is defective and worsens over time.^[31] Using a human induced pluripotent stem cell model of NHEJ1 deficiency, it was shown that NHEJ1 has an important role in promoting survival of the primitive hematopoietic progenitors.^[32] 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.^[32]

The sensitivity of hematopoietic stem cells to Lig4, DNA polymerase mu and NHEJ1 deficiency suggests that NHEJ is a key determinant of the ability of stem cells to maintain themselves against physiological stress over time.^[28] Rossi et al.^[33] found that endogenous DNA damage accumulates with age even in wild type Hematopoietic stem cells, and suggested that DNA damage accrual may be an important physiological mechanism of stem cell aging.

Loss of clonal diversity

A study shows the clonal diversity of hematopoietic stem cells gets drastically reduced around age 70 to a faster-growing few, substantiating a novel theory of ageing which could enable healthy aging.^[34][35] Of note, the shift in clonal diversity during aging was previously reported in 2008^[36] for the murine system by the Christa Muller-Sieburg laboratory in San Diego, California.

Research

Behavior in culture

A cobblestone area-forming cell (CAFC)

The reconstitution kinetics are very heterogeneous. However, using symbolic dynamics, one can show that they fall into a limited number of classes.^[39] To prove this, several hundred experimental repopulation kinetics from clonal Thy-1^lo SCA-1⁺ lin⁻(B220, CD4, CD8, Gr-1, Mac-1 and Ter-119)^[40] c-kit⁺ HSC were translated into symbolic sequences by assigning the symbols "+", "-", "~" whenever two successive measurements of the percent donor-type cells have a positive, negative, or unchanged slope, respectively. By using the Hamming distance, the repopulation patterns were subjected to cluster analysis yielding 16 distinct groups of kinetics. To finish the empirical proof, the Laplace add-one approach was used to determine that the probability of finding kinetics not contained in these 16 groups is very small. By corollary, this result shows that the hematopoietic stem cell compartment is also heterogeneous by dynamical criteria.

It was originally believed that all hematopoietic stem cells were alike in their self-renewal and differentiation abilities. This view was first challenged by the 2002 discovery by the

The results of these clonal studies led to the notion of lineage bias. Using the ratio ${\displaystyle \rho =L/M}$ of lymphoid (L) to myeloid (M) cells in blood as a quantitative marker, the stem cell compartment can be split into three categories of HSC. Balanced (Bala) hematopoietic stem cells repopulate peripheral white blood cells in the same ratio of myeloid to lymphoid cells as seen in unmanipulated mice (on average about 15% myeloid and 85% lymphoid cells, or 3 ≤ ρ ≤ 10). Myeloid-biased (My-bi) hematopoietic stem cells give rise to very few lymphocytes resulting in ratios 0 < ρ < 3, while lymphoid-biased (Ly-bi) hematopoietic stem cells generate very few myeloid cells, which results in lymphoid-to-myeloid ratios of ρ > 10. All three types are normal types of HSC, and they do not represent stages of differentiation. Rather, these are three classes of HSC, each with an epigenetically fixed differentiation program. These studies also showed that lineage bias is not stochastically regulated or dependent on differences in environmental influence. My-bi HSC self-renew longer than balanced or Ly-bi HSC. The myeloid bias results from reduced responsiveness to the lymphopoetin

Subsequently, other groups confirmed and highlighted the original findings.^[44] For example, the Eaves group confirmed in 2007 that repopulation kinetics, long-term self-renewal capacity, and My-bi and Ly-bi are stably inherited intrinsic HSC properties.^[45] In 2010, the Goodell group provided additional insights about the molecular basis of lineage bias in side population (SP) SCA-1⁺ lin⁻ c-kit⁺ HSC.^[46] As previously shown for IL-7 signaling, it was found that a member of the transforming growth factor family (TGF-beta) induces and inhibits the proliferation of My-bi and Ly-bi HSC, respectively.

Etymology

From Greek haimato-, combining form of haima 'blood', and from the Latinized form of Greek poietikos 'capable of making, creative, productive', from poiein 'to make, create'.^[47]

See also

• Hematopoietic stem cell niche
• List of distinct cell types in the adult human body

References