Steady state peripheral blood provides cells with functional and metabolic characteristics of real hematopoietic stem cells

2017 ◽  
Vol 233 (1) ◽  
pp. 338-349 ◽  
Author(s):  
Antonin Bourdieu ◽  
Maryse Avalon ◽  
Véronique Lapostolle ◽  
Sadek Ismail ◽  
Margaux Mombled ◽  
...  
Keyword(s):  
Stem Cells ◽  
Steady State ◽  
Hematopoietic Stem Cells ◽  
Peripheral Blood ◽  
Hematopoietic Stem ◽  
Metabolic Characteristics

scholarly journals Long-term repopulating hematopoietic stem cells and “side population” in human steady state peripheral blood

2013 ◽  
Vol 11 (1) ◽  
pp. 625-633 ◽  
Author(s):  
Philippe Brunet de la Grange ◽  
Marija Vlaski ◽  
Pascale Duchez ◽  
Jean Chevaleyre ◽  
Veronique Lapostolle ◽  
...  
Keyword(s):  
Stem Cells ◽  
Steady State ◽  
Hematopoietic Stem Cells ◽  
Peripheral Blood ◽  
Side Population ◽  
Hematopoietic Stem

Direct Comparison of Steady-State Marrow, Primed Marrow, and Mobilized Peripheral Blood for Transduction of Hematopoietic Stem Cells in Dogs

2003 ◽  
Vol 14 (17) ◽  
pp. 1683-1686 ◽  
Author(s):  
Bobbie Thomasson ◽  
Laura Peterson ◽  
Jesse Thompson ◽  
Martin Goerner ◽  
Hans-Peter Kiem
Keyword(s):  
Stem Cells ◽  
Steady State ◽  
Hematopoietic Stem Cells ◽  
Peripheral Blood ◽  
Hematopoietic Stem ◽  
Mobilized Peripheral Blood

Cell-Intrinsic and Cell-Extrinsic Involvement Of C/EBPβ In The Regulation Of Hematopoietic Stem Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1202-1202
Author(s):  
Akihiro Tamura ◽  
Hideyo Hirai ◽  
Yoshihiro Hayashi ◽  
Asumi Yokota ◽  
Atsushi Sato ◽  
...  
Keyword(s):  
Stem Cells ◽  
Steady State ◽  
Hematopoietic Stem Cells ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Leucine Zipper ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Hematopoietic Stem ◽  
The Difference

Abstract Our previous findings have revealed the requirement of CCAAT Enhancer Binding Protein β (C/EBPβ), a leucine zipper transcription factor, in emergency granulopoiesis (Hirai et al. Nat Immunol, 2006). During emergency situations such as infection, C/EBPβ is involved in the sufficient supply of granulocytes through amplification of hematopoietic stem/progenitor cells (Satake et al. J Immunol, 2012). In addition, we have shown that C/EBPβ is upregulated by downstream signaling of BCR-ABL and promotes myeloid expansion and leukemic stem cells exhaustion in chronic phase chronic myeloid leukemia (Hayashi et al. Leukemia, 2013). These observations suggested that C/EBPβ plays important roles in normal hematopoietic stem cells (HSCs). Here we investigated the cell-intrinsic and -extrinsic function of C/EBPβ in the regulation of HSCs by analyzing C/EBPβ knockout (KO) mice. At steady state, no obvious defects have been reported in hematopoiesis of C/EBPβ KO mice. Accordingly, the frequencies of long-term and short-term HSCs and various kinds of progenitor cells in bone marrows (BM) of C/EBPβ KO mice were identical to those in BM of wild type (WT) mice. To examine the functional consequences of C/EBPβ deletion, competitive repopulation assay was performed. In brief, 5x105 BM cells from WT or C/EBPβ KO mice (CD45.2+) and the same number of competitor CD45.1+ BM cells were transplanted into lethally irradiated CD45.1+ mice and the chimerisms of CD45.2+ cells in the peripheral blood of the recipient mice were monitored monthly. The chimerisms of C/EBPβ KO cells were significantly lower than that of WT cell at 1 month after transplantation and the differences were maintained thereafter (Figure A). In order to elucidate the reason for the difference, homing ability of C/EBPβ KO cells were assessed. Lineage depleted CD45.2+ WT or C/EBPβ KO BM cells together with the equal number of lineage negative CD45.1+ BM cells were transplanted into lethally irradiated CD45.1+ mice and the frequencies of CD45.2+ cells were analyzed 16 hours after transplantation. The frequencies of CD45.2+ WT and C/EBPβ KO donor cells in the recipient BMs were identical and the data indicated that the differences in the chimerisms after primary BM transplantation were due to the difference in the initial expansion of transplanted cells after equivalent levels of homing. To see the roles of C/EBPβ in hematopoiesis under stressed conditions, CD45.1+ mice were transplanted with CD45.2+ WT or C/EBPβ KO BM cells with equal numbers of CD45.1+ BM cells and these mice were administered with 150mg/kg 5-fluorouracil (5-FU) once a month and the chimerisms of peripheral blood were monitored every time before the next 5-FU administration. In consistent with the results mentioned above, the frequencies of CD45.2+ C/EBPβ KO cells were significantly lower than those of CD45.2+ WT cells 1 month after transplantation. After repetitive administration of 5-FU, however, the chimerisms of CD45.2+ C/EBPβ KO cells gradually caught up with those of CD45.2+ WT cells, suggesting that C/EBPβ is involved in the exhaustion of HSCs under stressed conditions (Figure B). To explore the functions of C/EBPβ in hematopoietic microenvironments, 1x106 CD45.1+ BM cells from WT mice were transplanted into irradiated (5Gy or 7Gy) WT or C/EBPβ KO mice (CD45.2+). All the WT recipient mice survived after 5Gy or 7Gy irradiation (4/4 and 4/4, respectively). In contrast, only 2/4 and 1/4 C/EBPβ KO recipient mice survived after 5Gy or 7Gy irradiation, respectively. We are currently trying to identify the cells expressing C/EBPβ in BM microenvironments and investigating the mechanisms for the higher sensitivity of C/EBPβ KO mice to irradiation. In summary, these data suggested that C/EBPβ is required for initial expansion of hematopoietic stem/progenitor cells at the expense of HSCs under stressed conditions, while it is dispensable for maintenance of HSCs at steady state. We are now investigating the cellular and molecular targets of C/EBPβ in HSC regulation and would like to elucidate the cell-intrinsic and cell-extrinsic mechanisms in regulation of the homeostasis of hematopoietic system by C/EBPβ. Disclosures: No relevant conflicts of interest to declare.

scholarly journals EPCR Signaling Controls the Activity of Hematopoietic Stem Cells Independent of Coagulation Regulation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3263-3263
Author(s):  
Son Nguyen ◽  
Divij Verma ◽  
Claudine Graf ◽  
Shiri Gur-Cohen ◽  
Jennifer Royce ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Steady State ◽  
Hematopoietic Stem Cells ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Hematopoietic Stem ◽  
Anticoagulant Function ◽  
Acute Myeloid

Abstract Background All mature blood cells are derived from multipotent hematopoietic stem cells (HSCs) which are activated to meet the demand of the host during inflammation and injury. The endothelial cell protein C receptor (EPCR) is a marker for primitivity and quiescence of HSCs but the relative contributions of EPCR signaling versus anticoagulant functions in HSC maintenance are incompletely defined. Aims We aimed to dissect functions of EPCR by studying anticoagulant and signaling function in HSC of EPCR C/S mice carrying a single intracellular point mutation abolishing normal trafficking of EPCR through endo-lysosomal compartments. We assessed the contributions of EPCR signaling to stem cell maintenance by analyzing HSC mobilization and leukemia progression. Methods We studied the frequency and cell cycle activity of bone marrow (BM) hematopoietic stem and progenitor cells (HSPC) by multicolor flow cytometry. Furthermore, we analyzed changes in hematopoiesis in steady state, after granulocyte colony stimulating factor (G-CSF)-induced mobilization, in the context of aging and in the context of leukemia, using the MLL-AF9-induced acute myeloid leukemia (AML) model. Results HSCs, lungs and isolated lung-derived smooth muscle cells of EPCR C/S mice showed protein expression levels and anticoagulant function indistinguishable from wildtype (WT). We found an increase of circulating HSCs in the peripheral blood of EPCR C/S mice compared to control under steady state conditions. Isolated HSC displayed diminished polarization of CDC42 and VLA-4 (α 4β 1 integrin) affinity to VCAM-1 in EPCR C/S versus strain-matched EPCR wt mice, indicating that EPCR signaling directly controls HSC retention via integrin affinity to the BM niche. In addition, we noticed a higher cell cycle activity in myeloid-restricted progenitors of EPCR C/S mice compared to control. G-CSF treatment led to increased mobilization of both BM neutrophils and HSCs into the peripheral blood of EPCR C/S mice compared to EPCR wt mice. A myeloid bias was also seen in serially transplanted aged mice, resulting in increased frequencies of myeloid-biased progenitors in the BM of EPCR C/S mice compared to control mice, accompanied by an increase of circulating neutrophils in the blood. Consistent with higher cell cycle activity of myeloid progenitors and an overall increase of myeloid-biased output in EPCR C/S mice, induction of AML by retroviral transduction of EPCR C/S BM cells with MLL-AF9-expressing retrovirus resulted in an increase of cell cycle activity of Lin - MLL-AF9 + leukemic BM blasts and a higher leukemic load in the peripheral blood of mice transplanted with MLL-AF9 + EPCR C/S BM compared to control. As a result, MLL-AF9 + EPCR C/S leukemia showed a more aggressive disease with shortened survival times compared to control. In contrast, chemotherapy of MLL-AF9 + EPCR C/S leukemia reduced leukemic load in the peripheral blood and decelerated disease progression. These data demonstrate that increased leukemia cell cycle activity conferred chemosensitivity. Conclusion With a site-specific EPCR mutant knock-in mouse, we here demonstrate that EPCR signaling and anticoagulant function can be separated. We provide direct evidence that EPCR signaling plays a crucial role in maintaining HSC retention via VLA-4 affinity to VCAM-1, controls cell cycle activity and myeloid output in normal, stress-induced, and malignant hematopoiesis with implications for therapeutic approaches in acute myeloid leukemia. Disclosures Ruf: MeruVasimmune: Other: Ownership Interest; ARCA bioscience: Consultancy, Patents & Royalties; ICONIC Therapeutics: Consultancy.

UM171 promotes expansion of autologous peripheral blood hematopoietic stem cells from poorly mobilizing lymphoma patients

2020 ◽  
Vol 81 ◽  
pp. 106266
Author(s):  
Ruiting Wen ◽  
Chen Dong ◽  
Chen Xu ◽  
Long Zhao ◽  
Yang Yang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Peripheral Blood ◽  
Hematopoietic Stem

scholarly journals Lineage tracing of murine adult hematopoietic stem cells reveals active contribution to steady-state hematopoiesis

2018 ◽  
Vol 2 (11) ◽  
pp. 1220-1228 ◽  
Author(s):  
Richard H. Chapple ◽  
Yu-Jung Tseng ◽  
Tianyuan Hu ◽  
Ayumi Kitano ◽  
Makiko Takeichi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Steady State ◽  
Hematopoietic Stem Cells ◽  
Lineage Tracing ◽  
Lymphoid Cells ◽  
Hematopoietic Stem ◽  
Key Points ◽  
Active Contribution

Key Points HSCs contribute robustly to steady-state hematopoiesis. Platelets receive extensive influx from HSCs compared with other myeloid or lymphoid cells.

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