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Asymmetric division and lineage commitment at the level of hematopoietic stem cells: inference from differentiation in daughter cell and granddaughter cell pairs.

Takano H, Ema H, Sudo K, Nakauchi H - J. Exp. Med. (2004)

Bottom Line: Assuming that a substantial portion of long-term repopulating cells can be detected as nmEM cells within this population, we compared differentiation potentials between individual pairs of daughter and granddaughter cells derived in vitro from single nmEM cells.The probability of asymmetric division of nmEM cells depended on the cytokines used.These data strongly suggest that lineage commitment takes place asymmetrically at the level of HSCs under the influence of external factors.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Stem Cell Therapy, Center for Experimental Medicine, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, 108-8639, Japan.

ABSTRACT
How hematopoietic stem cells (HSCs) commit to a particular lineage is unclear. A high degree of HSC purification enabled us to address this issue at the clonal level. Single-cell transplantation studies revealed that 40% of the CD34-/low, c-Kit+, Sca-1+, and lineage marker- (CD34-KSL) cells in adult mouse bone marrow were able, as individual cells, to reconstitute myeloid and B- and T-lymphoid lineages over the long-term. Single-cell culture showed that >40% of CD34-KSL cells could form neutrophil (n)/macrophage (m)/erythroblast (E)/megakaryocyte (M) (nmEM) colonies. Assuming that a substantial portion of long-term repopulating cells can be detected as nmEM cells within this population, we compared differentiation potentials between individual pairs of daughter and granddaughter cells derived in vitro from single nmEM cells. One of the two daughter or granddaughter cells remained an nmEM cell. The other showed a variety of combinations of differentiation potential. In particular, an nmEM cell directly gave rise, after one cell division, to progenitor cells committed to nm, EM, or M lineages. The probability of asymmetric division of nmEM cells depended on the cytokines used. These data strongly suggest that lineage commitment takes place asymmetrically at the level of HSCs under the influence of external factors.

Show MeSH
Myeloid lineage restriction model. The mode of lineage commitment at the level of HSCs may differ from that at the level of progenitor cells. Our model for HSCs is presented in combination with the model proposed by Weissman's group (34). An HSC can directly give rise to lineage-committed progenitor cells such as nm, EM, or M progenitor cells through initial HSC division in asymmetric manner. It may give rise to a common myeloid progenitor (CMP) after a certain number of divisions. The CMP gives rise to a megakaryocyte/erythrocyte lineage–restricted progenitor (MEP) and to a granulocyte/macrophage lineage-restricted progenitor (GMP). The MEP progressively gives rise to a megakaryocyte-committed progenitor (MKP) and to an erythrocyte lineage-committed progenitor (ErP). P, probability of asymmetric division.
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fig4: Myeloid lineage restriction model. The mode of lineage commitment at the level of HSCs may differ from that at the level of progenitor cells. Our model for HSCs is presented in combination with the model proposed by Weissman's group (34). An HSC can directly give rise to lineage-committed progenitor cells such as nm, EM, or M progenitor cells through initial HSC division in asymmetric manner. It may give rise to a common myeloid progenitor (CMP) after a certain number of divisions. The CMP gives rise to a megakaryocyte/erythrocyte lineage–restricted progenitor (MEP) and to a granulocyte/macrophage lineage-restricted progenitor (GMP). The MEP progressively gives rise to a megakaryocyte-committed progenitor (MKP) and to an erythrocyte lineage-committed progenitor (ErP). P, probability of asymmetric division.

Mentions: Interestingly, we did not observe the combination of nm lineage and EM lineage in a total of 154 pairs of daughter and granddaughter cells (Tables II and III). A CMP has been described as giving rise to separate colonies of nm lineage and EM lineage in culture, with EM lineage–committed progenitors, in turn, giving rise to E lineage–committed progenitors and M lineage–committed progenitors, supporting a progressive loss of differentiation potential (34). Our data suggest an alternative pathway of myeloerythroid differentiation in which nm or EM progenitor cells can asymmetrically develop from an HSC population with no need for a CMP intermediate (Fig. 4). The modes of lineage commitment possibly differ between stem and progenitor cell compartments.


Asymmetric division and lineage commitment at the level of hematopoietic stem cells: inference from differentiation in daughter cell and granddaughter cell pairs.

Takano H, Ema H, Sudo K, Nakauchi H - J. Exp. Med. (2004)

Myeloid lineage restriction model. The mode of lineage commitment at the level of HSCs may differ from that at the level of progenitor cells. Our model for HSCs is presented in combination with the model proposed by Weissman's group (34). An HSC can directly give rise to lineage-committed progenitor cells such as nm, EM, or M progenitor cells through initial HSC division in asymmetric manner. It may give rise to a common myeloid progenitor (CMP) after a certain number of divisions. The CMP gives rise to a megakaryocyte/erythrocyte lineage–restricted progenitor (MEP) and to a granulocyte/macrophage lineage-restricted progenitor (GMP). The MEP progressively gives rise to a megakaryocyte-committed progenitor (MKP) and to an erythrocyte lineage-committed progenitor (ErP). P, probability of asymmetric division.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211802&req=5

fig4: Myeloid lineage restriction model. The mode of lineage commitment at the level of HSCs may differ from that at the level of progenitor cells. Our model for HSCs is presented in combination with the model proposed by Weissman's group (34). An HSC can directly give rise to lineage-committed progenitor cells such as nm, EM, or M progenitor cells through initial HSC division in asymmetric manner. It may give rise to a common myeloid progenitor (CMP) after a certain number of divisions. The CMP gives rise to a megakaryocyte/erythrocyte lineage–restricted progenitor (MEP) and to a granulocyte/macrophage lineage-restricted progenitor (GMP). The MEP progressively gives rise to a megakaryocyte-committed progenitor (MKP) and to an erythrocyte lineage-committed progenitor (ErP). P, probability of asymmetric division.
Mentions: Interestingly, we did not observe the combination of nm lineage and EM lineage in a total of 154 pairs of daughter and granddaughter cells (Tables II and III). A CMP has been described as giving rise to separate colonies of nm lineage and EM lineage in culture, with EM lineage–committed progenitors, in turn, giving rise to E lineage–committed progenitors and M lineage–committed progenitors, supporting a progressive loss of differentiation potential (34). Our data suggest an alternative pathway of myeloerythroid differentiation in which nm or EM progenitor cells can asymmetrically develop from an HSC population with no need for a CMP intermediate (Fig. 4). The modes of lineage commitment possibly differ between stem and progenitor cell compartments.

Bottom Line: Assuming that a substantial portion of long-term repopulating cells can be detected as nmEM cells within this population, we compared differentiation potentials between individual pairs of daughter and granddaughter cells derived in vitro from single nmEM cells.The probability of asymmetric division of nmEM cells depended on the cytokines used.These data strongly suggest that lineage commitment takes place asymmetrically at the level of HSCs under the influence of external factors.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Stem Cell Therapy, Center for Experimental Medicine, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, 108-8639, Japan.

ABSTRACT
How hematopoietic stem cells (HSCs) commit to a particular lineage is unclear. A high degree of HSC purification enabled us to address this issue at the clonal level. Single-cell transplantation studies revealed that 40% of the CD34-/low, c-Kit+, Sca-1+, and lineage marker- (CD34-KSL) cells in adult mouse bone marrow were able, as individual cells, to reconstitute myeloid and B- and T-lymphoid lineages over the long-term. Single-cell culture showed that >40% of CD34-KSL cells could form neutrophil (n)/macrophage (m)/erythroblast (E)/megakaryocyte (M) (nmEM) colonies. Assuming that a substantial portion of long-term repopulating cells can be detected as nmEM cells within this population, we compared differentiation potentials between individual pairs of daughter and granddaughter cells derived in vitro from single nmEM cells. One of the two daughter or granddaughter cells remained an nmEM cell. The other showed a variety of combinations of differentiation potential. In particular, an nmEM cell directly gave rise, after one cell division, to progenitor cells committed to nm, EM, or M lineages. The probability of asymmetric division of nmEM cells depended on the cytokines used. These data strongly suggest that lineage commitment takes place asymmetrically at the level of HSCs under the influence of external factors.

Show MeSH