Multipotent Hematopoietic Progenitors Divide Asymmetrically to Create Progenitors of the Lymphomyeloid and Erythromyeloid Lineages

Görgens, André; Ludwig, Anna‐Kristin; Möllmann, Michael; Krawczyk, Adalbert; Dürig, Jan; Horn, Peter A.; Giebel, Bernd

doi:10.1016/j.stemcr.2014.09.016

Cited by 41 publications

(30 citation statements)

References 35 publications

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“…We sort-purified all four CD34 subpopulations, cultured them for three days and then analyzed the progeny by flow cytometry (Figure 2A–C). Similar to UCB and PBSCs (Figure 2B–C and [4]), only HSCs/MPPs from FL gave rise to LMPPs, EMPs and GMPs (Figure 2A). In contrast to UCB and PBSC-derived HSC/MPP fractions which predominantly give rise to LMPPs within similar growth conditions (Figure 2B–C and [4]), the majority of FL-derived HSCs/MPPs differentiated into EMPs (Figure 2A).…”

Section: Resultsmentioning

confidence: 82%

“…Similar to UCB and PBSCs (Figure 2B–C and [4]), only HSCs/MPPs from FL gave rise to LMPPs, EMPs and GMPs (Figure 2A). In contrast to UCB and PBSC-derived HSC/MPP fractions which predominantly give rise to LMPPs within similar growth conditions (Figure 2B–C and [4]), the majority of FL-derived HSCs/MPPs differentiated into EMPs (Figure 2A). To confirm that FL-HSCs/MPPs can give rise to functional LMPPs and EMPs, arising daughter cells were plated into CFC assays.…”

Section: Resultsmentioning

confidence: 82%

“…Within adult stem cell sources, HSC/MPP have been shown to divide asymmetrically giving rise to a LMPP and EMP daughter cell [4]. Thus we wished to determine whether FL-derived HSCs/MPPs would also serve as precursors of LMPPs and EMPs.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, the frequency of BM-resident multipotent CD133 + CD45RA − with CFU-MIX potential [4] was very low (Figure 3J) with a calculated frequency of 0.007 ± 0.003% (2.29% [CFU-Mix frequency] of 0.30% CD133 + CD45RA − HSPCs [Figure 3I]) in the bone marrow-resident human CD45 + cell fraction. Considering the high frequency of human CD45 + cell in the peripheral blood of engrafted mice, this suggests the observed engraftment was predominantly driven by committed progenitors, e.g.…”

Section: Resultsmentioning

confidence: 99%

“…These studies showed that CD133 + CD34 + CD45RA − cell fractions are highly enriched for hematopoietic stem cells and multipotent progenitor cells (HSCs/MPPs) giving rise to CD133 + CD34 + CD45RA + lympho-myeloid primed progenitors (LMPPs) and CD133 low CD34 + CD45RA − erythro-myeloid restricted progenitors (EMP, Figure 1A and B) [4]. This model further proposed that multipotent HSCs/MPPs could easily be identified as CD133-expressing cells with erythroid differentiation potential.…”

Section: Introductionmentioning

confidence: 99%

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The frequency of multipotent CD133+CD45RA−CD34+ hematopoietic stem cells is not increased in fetal liver compared with adult stem cell sources

Haworth

Kiem

2016

Experimental Hematology

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The cell surface marker CD133 has been used to describe a revised model of adult human hematopoiesis with hematopoietic stem cells and multipotent progenitors (HSCs/MPPs: CD133+CD45RA−CD34+) giving rise to a lympho-myeloid primed progenitor (LMPPs: CD133+CD45RA+CD34+) and an erythro-myeloid progenitor (EMPs: CD133lowCD45RA−CD34+). Since adult and fetal hematopoietic stem and progenitor cells (HSPCs) differ in their gene expression profile, differentiation capabilities, and cell surface marker expression, we were interested whether the reported segregation of lineage potentials in adult human hematopoiesis would also apply to the human fetal liver (FL). CD133 expression was easily detected on human FL cells, and the defined hematopoietic subpopulations were similar to the findings with adult HSPCs. Fetal HSPCs were enriched for EMPs and HSCs/MPPs, which were primed towards erythro-myeloid differentiation. However, the frequency of multipotent CD133+CD45RA−CD34+ HSPCs was much lower than previously reported and comparable to umbilical cord blood. We found that engraftment in NSG mice was mostly driven by LMPPs, confirming recent findings that repopulation in mice is not a unique feature of multipotent HSCs/MPPs. Thus, our data challenges the general assumption that the human FL contains a greater percentage of multipotent HSCs/MPPs than any adult HSC source, and the mouse model may have to be re-evaluated with regard to the type of readout it provides.

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Section: Resultsmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The frequency of multipotent CD133+CD45RA−CD34+ hematopoietic stem cells is not increased in fetal liver compared with adult stem cell sources

Haworth

Kiem

2016

Experimental Hematology

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Combination of imaging flow cytometry and time‐lapse microscopy for the study of label‐free morphology dynamics of hematopoietic cells

et al. 2017

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Cell differentiation is a longitudinal and dynamic process. Studying and quantifying such a process require tools combining precise time resolution and statistical power. Imaging flow cytometry (IFC) provides statistically significant number of microscopy images of individual cells in a sample at a given time point. Time-lapse microscopy (TLM) is the method of choice for studying the dynamics of cell processes at a high temporal, but low statistical resolution. In this work, we show that the dynamic changes of cord-blood derived CD34+ cells in response to cytokine stimulation can be successfully studied, in a label-free way, by the combination of the IFCs statistical power and the TLM's high time resolution. Cell morphology phenotypes were quantified through roundness and surface area, measured both in IFC and with a homemade segmentation algorithm in TLM. Two distinct morphologies-polarized and round-were observed in cord-blood derived CD34+. We show that some cells have the ability to fluctuate between these morphologies, suggesting that the apparent stable composition of round and polarized cells may actually represent a dynamic equilibrium. This example demonstrates that the different resolutions and modalities of IFC and TLM are complementary and allow the study of complex dynamic biological processes. © 2017 International Society for Advancement of Cytometry.

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Plerixafor as preemptive strategy results in high success rates in autologous stem cell mobilization failure

Worel

Fritsch

Agis

et al. 2016

J of Clinical Apheresis

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Plerixafor in combination with granulocyte-colony stimulating factor (G-CSF) is approved for autologous stem cell mobilization in poor mobilizing patients with multiple myeloma or malignant lymphoma. The purpose of this study was to evaluate efficacy and safety of plerixafor in an immediate rescue approach, administrated subsequently to G-CSF alone or chemotherapy and G-CSF in patients at risk for mobilization failure. Eighty-five patients mobilized with G-CSF alone or chemotherapy were included. Primary endpoint was the efficacy of the immediate rescue approach of plerixafor to achieve ≥2.0 × 10 CD34 cells/kg for a single or ≥5 × 10 CD34 cells/kg for a double transplantation and potential differences between G-CSF and chemotherapy-based mobilization. Secondary objectives included comparison of stem cell graft composition including CD34 cell and lymphocyte subsets with regard to the mobilization regimen applied. No significant adverse events were recorded. A median 3.9-fold increase in CD34 cells following plerixafor was observed, resulting in 97% patients achieving at least ≥2 × 10 CD34+ cells/kg. Significantly more differentiated granulocyte and monocyte forming myeloid progenitors were collected after chemomobilization whereas more CD19 and natural killer cells were collected after G-CSF. Fifty-two patients underwent transplantation showing rapid and durable engraftment, irrespectively of the stem cell mobilization regimen used. The addition of plerixafor in an immediate rescue model is efficient and safe after both, G-CSF and chemomobilization and results in extremely high success rates. Whether the differences in graft composition have a clinical impact on engraftment kinetics, immunologic recovery, and graft durability have to be analysed in larger prospective studies.

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Multipotent Hematopoietic Progenitors Divide Asymmetrically to Create Progenitors of the Lymphomyeloid and Erythromyeloid Lineages

Cited by 41 publications

References 35 publications

The frequency of multipotent CD133+CD45RA−CD34+ hematopoietic stem cells is not increased in fetal liver compared with adult stem cell sources

The frequency of multipotent CD133+CD45RA−CD34+ hematopoietic stem cells is not increased in fetal liver compared with adult stem cell sources

Combination of imaging flow cytometry and time‐lapse microscopy for the study of label‐free morphology dynamics of hematopoietic cells

Plerixafor as preemptive strategy results in high success rates in autologous stem cell mobilization failure

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