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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.

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Distribution of lineage-committed daughter and granddaughter cells. The numbers of daughter and granddaughter cells that lost the capacity to differentiate along one or more lineages are graphed, using data in Tables II and III. All possible combinations of differentiation potential are shown in the same order as that presented in Fig. 2.
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fig3: Distribution of lineage-committed daughter and granddaughter cells. The numbers of daughter and granddaughter cells that lost the capacity to differentiate along one or more lineages are graphed, using data in Tables II and III. All possible combinations of differentiation potential are shown in the same order as that presented in Fig. 2.

Mentions: This work clearly demonstrates an instructive role of cytokines in lineage commitment at the level of HSCs (Tables II and III). The probability of lineage commitment by nmEM cells in the presence of SCF + TPO was significantly lower than that in the presence of SCF + IL-3. The probability remained similar through the initial two divisions with SCF + IL-3 (0.62 and 0.58), but not with SCF + TPO (0.17 and 0.32). Lineage commitment by HSCs can be controlled to some extent by external factors. Whether cytokines also influence which lineage potential is chosen by HSCs upon their lineage commitment remains unclear. Fig. 3 presents the numbers of committed progenitor cells that appeared after the first and second divisions of nmEM cells. In the presence of either IL-3 or TPO, nmEM cells seemed to have a preference in lineage choice, suggesting that the fate decision of HSCs is not a random event. Alternatively, this may simply indicate postcommitment selection in given culture conditions.


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)

Distribution of lineage-committed daughter and granddaughter cells. The numbers of daughter and granddaughter cells that lost the capacity to differentiate along one or more lineages are graphed, using data in Tables II and III. All possible combinations of differentiation potential are shown in the same order as that presented in Fig. 2.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Distribution of lineage-committed daughter and granddaughter cells. The numbers of daughter and granddaughter cells that lost the capacity to differentiate along one or more lineages are graphed, using data in Tables II and III. All possible combinations of differentiation potential are shown in the same order as that presented in Fig. 2.
Mentions: This work clearly demonstrates an instructive role of cytokines in lineage commitment at the level of HSCs (Tables II and III). The probability of lineage commitment by nmEM cells in the presence of SCF + TPO was significantly lower than that in the presence of SCF + IL-3. The probability remained similar through the initial two divisions with SCF + IL-3 (0.62 and 0.58), but not with SCF + TPO (0.17 and 0.32). Lineage commitment by HSCs can be controlled to some extent by external factors. Whether cytokines also influence which lineage potential is chosen by HSCs upon their lineage commitment remains unclear. Fig. 3 presents the numbers of committed progenitor cells that appeared after the first and second divisions of nmEM cells. In the presence of either IL-3 or TPO, nmEM cells seemed to have a preference in lineage choice, suggesting that the fate decision of HSCs is not a random event. Alternatively, this may simply indicate postcommitment selection in given culture conditions.

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