Stem cell continuum: Directed differentiation hotspots

Colvin, Gerald A.; Dooner, Mark S.; Dooner, Gerri; Sánchez‐Guijo, Fermín; Demers, Delia; Abedi, Mehrdad; Ramanathan, Muthalagu; Chung, Samuel; Pascual, S.; Quesenberry, Peter J.

doi:10.1016/j.exphem.2006.09.005

Cited by 36 publications

(39 citation statements)

References 50 publications

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“…We have previously mapped the cell cycle status of LRH cells stimulated with thrombopoietin, FLT3L, and steel factor using propidium iodide [15]. At time 0, there are either very few or no LRH stem cells in S phase, and hence there is a highly synchronous progression through cycle.…”

Section: Isolation Of Whole Bone Marrowmentioning

confidence: 99%

“…Previous studies have further established a number of reversible functional phenotype shifts with cycle progression. We have shown that short-and long-term engraftment [9,10], adhesion protein expression [11,12], cytokine receptor expression [13], and marrow homing [14] and differentiation [15] show reversible shifts in phenotype. We have also shown that progenitor numbers vary inversely with engraftable stem cell content with cycle passage, terming this a stem cell inversion [16].…”

Section: Introductionmentioning

confidence: 99%

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Expression of Cell Cycle–Related Genes With Cytokine-Induced Cell Cycle Progression of Primitive Hematopoietic Stem Cells

Quesenberry

Dooner²,

Tatto³

et al. 2010

Stem Cells and Development

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Primitive marrow lineage-negative rhodamine low and Hoechst low (LRH) stem cells isolated on the basis of quiescence respond to the cytokines thrombopoietin, FLT3L, and steel factor by synchronously progressing through cell cycle. We have now profi led the mRNA expression, as determined by real-time RT-PCR, of 47 hematopoietic or cell cycle-related genes, focusing on the variations in the cell cycle regulators with cycle transit. LRH stem cells, at isolation, showed expression of all interrogated genes, but at relatively low levels. In our studies, there was a good deal of consistency with regard to cell cycle regulatory genes involved in the G1/S progression point of LRH murine stem cells. The observed pattern of expression of cyclin A2 is consistent with actions at these phases of cell cycle. Minimal elevations were seen at 16 h with higher elevations at 24, 32, 40, and 48 h times encompassing S, G2, and M phases. CDK2 expression pattern was also consistent with a role in G1/S transition with a modest elevation at 24 h and more substantial elevation at 32 h. The observed pattern of expression of cyclin F mRNA with marked elevations at 16-40 h was also consistent with actions in S and G2 phases. Cyclin D1 expression pattern was less consistent with its known role in G1 progression. The alterations in multiple other cell cycle regulators were consistent with previous information obtained in other cell systems. The cycle regulatory mechanics appears to be preserved across broad ranges of cell types.

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Section: Isolation Of Whole Bone Marrowmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression of Cell Cycle–Related Genes With Cytokine-Induced Cell Cycle Progression of Primitive Hematopoietic Stem Cells

Quesenberry

Dooner²,

Tatto³

et al. 2010

Stem Cells and Development

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“…As engraftment potential is significantly better in cells prior to and after late S/early G2 phase, then nadirs again at the next late S/early G2 phase, these changes appear to be reversible. Their fluctuating differentiative potential results in the production of populations of specific lineages of differentiated hematopoietic cells depending on where they are in cell cycle as we have shown that HSCs at early S phase and mid S phase give rise to megakaryocytic and nonproliferative granulocytic-predominant populations (respectively) of differentiated cells in secondary culture [3]. These observations have led to the continuum model of stem cell biology, in which the differentiation potential of HSCs is linked to cell cycle [15][16][17][18][19][20][21][22][23].…”

mentioning

confidence: 99%

“…With subsequent divisions, daughter cells obtain more differentiated characteristics and lose self-renewal potential. Contrary to this model, our group has shown that HSC are capable of reversibly changing their functional phenotype as they progress though cell cycle [1][2][3][4][5][6][7][8][9][10][11][12][13]. We have used cocktails of cytokines including interleukins (ILs)-3, 6, and 11 and stem cell factor (SCF) or SCF, thrombopoietin, and FLK-2, to induce HSC to progress though cell cycle in a synchronous fashion.…”

mentioning

confidence: 99%

Progenitor/Stem Cell Fate Determination: Interactive Dynamics of Cell Cycle and Microvesicles

Aliotta

Lee

Puente

et al. 2012

Stem Cells and Development

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We have shown that hematopoietic stem/progenitor cell phenotype and differentiative potential change throughout cell cycle. Lung-derived microvesicles (LDMVs) also change marrow cell phenotype by inducing them to express pulmonary epithelial cell-specific mRNA and protein. These changes are accentuated when microvesicles isolated from injured lung. We wish to determine if microvesicle-treated stem/progenitor cell phenotype is linked to cell cycle and to the injury status of the lung providing microvesicles. Lineage depleted, Sca-1 + (Lin-/Sca-1 + ) marrow isolated from mice were cultured with interleukin 3 (IL-3), IL-6, IL-11, and stem cell factor (cytokine-cultured cells), removed at hours zero (cell cycle phase G0/G1), 24 (late G1/early S), and 48 (late S/early G2/M), and cocultured with lung tissue, lung conditioned media (LCM), or LDMV from irradiated or nonirradiated mice. Alternatively, Lin-/Sca-1 + cells not exposed to exogenous cytokines were separated into G0/G1 and S/G2/M cell cycle phase populations by fluorescence-activated cell sorting (FACS) and used in coculture. Separately, LDMV from irradiated and nonirradiated mice were analyzed for the presence of adhesion proteins. Peak pulmonary epithelial cell-specific mRNA expression was seen in G0/G1 cytokine-cultured cells cocultured with irradiated lung and in late G1/early S cells cocultured with nonirradiated lung. The same pattern was seen in cytokine-cultured Lin-/Sca-1 cells cocultured with LCM and LDMV and when FACSseparated Lin-/Sca-1 cells unexposed to exogenous cytokines were used in coculture. Cells and LDMV expressed adhesion proteins whose levels differed based on cycle status (cells) or radiation injury (LDMV), suggesting a mechanism for microvesicle entry. These data demonstrate that microvesicle modification of progenitor/stem cells is influenced by cell cycle and the treatment of the originator lung tissue.

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“…9 In addition, by interrogating the stem cell capacity and cell cycle status of distinct subpopulations of marrow cells typically discarded during conventional stem cell isolation strategies, we have found that both the lineage-positive and lineage-negative cellular fractions contain actively cycling stem cells and that these cycling stem cells appear to be preferentially lost in standard HSC purifications. 9 Numerous older studies have shown fluctuations in stem cell homing, differentiation and engraftment capacity linked to cell cycle transit [10][11][12] and we postulate that, if marrow stem cells are cycling, they cannot be purified to 'homogeneity' as they will be continually changing their phenotype as they transit the cell cycle. We are embarking on studies tracking stem cell marker fluctuation with cell cycle progression.…”

mentioning

confidence: 99%

Reconsidering marrow stem cell cycle status: insights into an actively cycling hematopoietic stem cell population

Goldberg

2014

Leukemia Suppl

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Stem cell continuum: Directed differentiation hotspots

Cited by 36 publications

References 50 publications

Expression of Cell Cycle–Related Genes With Cytokine-Induced Cell Cycle Progression of Primitive Hematopoietic Stem Cells

Expression of Cell Cycle–Related Genes With Cytokine-Induced Cell Cycle Progression of Primitive Hematopoietic Stem Cells

Progenitor/Stem Cell Fate Determination: Interactive Dynamics of Cell Cycle and Microvesicles

Reconsidering marrow stem cell cycle status: insights into an actively cycling hematopoietic stem cell population

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