Sphingosine-1-phosphate facilitates trafficking of hematopoietic stem cells and their mobilization by CXCR4 antagonists in mice

Blood ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. 707-716 ◽  
Author(s):  
Julius G. Juarez ◽  
Nadia Harun ◽  
Marilyn Thien ◽  
Robert Welschinger ◽  
Rana Baraz ◽  
...  
Keyword(s):  
Stem Cells ◽  
Steady State ◽  
Hematopoietic Stem Cells ◽  
Progenitor Cell ◽  
Hematopoietic Progenitors ◽  
Cxcr4 Antagonist ◽  
Hematopoietic Stem ◽  
Sphingosine 1 Phosphate ◽  
Cxcr4 Antagonists ◽  
Cell Mobilization

Abstract CXCL12 and VCAM1 retain hematopoietic stem cells (HSCs) in the BM, but the factors mediating HSC egress from the BM to the blood are not known. The sphingosine-1-phosphate receptor 1 (S1P1) is expressed on HSCs, and S1P facilitates the egress of committed hematopoietic progenitors from the BM into the blood. In the present study, we show that both the S1P gradient between the BM and the blood and the expression of S1P1 are essential for optimal HSC mobilization by CXCR4 antagonists, including AMD3100, and for the trafficking of HSCs during steady-state hematopoiesis. We also demonstrate that the S1P1 agonist SEW2871 increases AMD3100-induced HSC and progenitor cell mobilization. These results suggest that the combination of a CXCR4 antagonist and a S1P1 agonist may prove to be sufficient for mobilizing HSCs in normal donors for transplantation purposes, potentially providing a single mobilization procedure and eliminating the need to expose normal donors to G-CSF with its associated side effects.

Rapid mobilization of murine hematopoietic stem cells with enhanced engraftment properties and evaluation of hematopoietic progenitor cell mobilization in rhesus monkeys by a single injection of SB-251353, a specific truncated form of the human CXC chemokine GROβ

Blood ◽  
2001 ◽  
Vol 97 (6) ◽  
pp. 1534-1542 ◽  
Author(s):  
Andrew G. King ◽  
Dan Horowitz ◽  
Susan B. Dillon ◽  
Robert Levin ◽  
Ann M. Farese ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Peripheral Blood ◽  
Rhesus Monkeys ◽  
Progenitor Cell ◽  
Single Injection ◽  
Hematopoietic Progenitor ◽  
Hematopoietic Stem ◽  
Cell Mobilization

SB-251353 is an N-terminal truncated form of the human CXC chemokine GROβ. Recombinant SB-251353 was profiled in murine and rhesus monkey peripheral blood stem cell mobilization and transplantation models. SB-251353 rapidly and transiently mobilized hematopoietic stem cells and neutrophils into the peripheral blood after a single subcutaneous injection. Transplantation of equivalent numbers of hematopoietic stem cells mobilized by SB-251353 into lethally irradiated mice resulted in faster neutrophil and platelet recovery than stem cells mobilized by granulocyte colony-stimulating factor (G-CSF). A single injection of SB-251353 in combination with 4 days of G-CSF administration resulted in augmented stem and progenitor cell mobilization 5-fold greater than G-CSF alone. Augmented stem cell mobilization could also be demonstrated in mice when a single injection of SB-251353 was administered with only one-day treatment with G-CSF. In addition, SB-251353, when used as a single agent or in combination with G-CSF, mobilized long-term repopulating stem cells capable of hematopoietic reconstitution of lethally irradiated mice. In rhesus monkeys, a single injection of SB-251353 induced rapid increases in peripheral blood hematopoietic progenitor cells at a 50-fold lower dose than in mice, which indicates a shift in potency. These studies provide evidence that the use of SB-251353 alone or in combination with G-CSF mobilizes hematopoietic stem cells with long-term repopulating ability. In addition, this treatment may (1) reduce the number of apheresis sessions and/or amount of G-CSF required to collect adequate numbers of hematopoietic stem cells for successful peripheral blood cell transplantation and (2) improve hematopoietic recovery after transplantation.

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

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.

Long-term-repopulating hematopoietic stem cells are dispensable in steady state but essential for stress hematopoiesis

2015 ◽  
Vol 43 (9) ◽  
pp. S94 ◽  
Author(s):  
Alexander Gerbaulet ◽  
Kristina Schoedel ◽  
Thomas Zerjatke ◽  
Ingo Roeder ◽  
David Voehringer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Steady State ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem

scholarly journals Self-Renewal of Single Mouse Hematopoietic Stem Cells Is Reduced by JAK2V617F Without Compromising Progenitor Cell Expansion

PLoS Biology ◽  
2013 ◽  
Vol 11 (6) ◽  
pp. e1001576 ◽  
Author(s):  
David G. Kent ◽  
Juan Li ◽  
Hinal Tanna ◽  
Juergen Fink ◽  
Kristina Kirschner ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Expansion ◽  
Progenitor Cell ◽  
Self Renewal ◽  
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

Intercommunication Between C-Myc and PTEN in the Regulation of Hematopoietic Stem Cell-Niche Interactions and Hematopoietic Progenitor Cell Lineage Commitment.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1408-1408
Author(s):  
Yinshi Guo ◽  
Chao Niu ◽  
Peter Breslin ◽  
Shubin Zhang ◽  
Wei Wei ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Knockout Mice ◽  
Progenitor Cell ◽  
Gene Knockout ◽  
Lineage Commitment ◽  
Hematopoietic Stem ◽  
Bm Niche ◽  
Pten Deletion ◽  
Gene Knockout Mice

Abstract It was shown that c-Myc is required for the proliferation and differentiation of hematopoietic stem cells and progenitors. Mice with c-Myc deletions develop severe anemia and cytopenia. However, hematopoietic stem cells (HSCs) accumulate in significant numbers in the bone marrow (BM) of mutant mice, probably due to an increase in adhesiveness of the mutant HSCs to BM osteoblastic niche cells. Previously, we demonstrated that PTEN might play a critical role in the process of adhesion of HSCs to BM niche cells. Deletion of PTEN results in the proliferation and peripheral mobilization of HSCs, followed by a decline in these cells. PTEN mutant mice proceed to develop myeloproliferative disorders. Here we report that c-Myc also has an essential role to play in regulating the lineage commitment of HSCs and progenitors (HSC/Ps). HSC/Ps in which c-Myc is deleted are biased toward megakaryocytic lineage differentiation at the expense of other lineages. c-Myc knockout mice develop significant thrombocytosis (3- to 5-fold increase in peripheral platelet numbers) due to an obviously increased megakaryopoiesis in BM and spleen. PTEN deletion causes down-regulation of expression of adhesive molecules, including integrins and N-cadherin, in HSCs, resulting not only in an increased mobilization of c-Myc-mutant HSCs from the BM niche but also mobilization of c-Myc-mutant megakaryocytic progenitors to the spleen. We found that HSCs and megakaryocytic progenitors are significantly reduced in BM but dramatically increased in the spleens of PTEN/c-MYC double-knockout mice, compared to c-Myc single-gene knockout mice. In addition, PTEN deletion further promotes megakaryocytic progenitor cell proliferation, as well as infiltration of these cells into the liver. PTEN/c-Myc double-gene knockout mice consistently develop megakaryocytic proliferative disorders. We conclude that the ability of c-Myc to regulate HSC-BM niche interactions is at least partially accomplished through inhibition of PTEN function by c-Myc. In addition, c-Myc controls the lineage commitment of HSC/Ps. Deletion of c-Myc converts the myeloproliferative disorder seen in PTEN knockout mice to a megakaryocytic proliferative disorder. Whether PTEN and c-Myc mutations are likewise etiologically involved in human megakaryocytic proliferative disorders and megakaryocytic leukemia is currently a topic of active investigation in our laboratory.

Cyclin A2 Plays a Critical Role Not Only in Self-Renewal of Hematopoietic Stem Cells, but Also in Non-Self-Renewing Proliferation of Lymphoid Progenitors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 381-381 ◽  
Author(s):  
Kentaro Kohno ◽  
Tadafumi Iino ◽  
Kyoko Ito ◽  
Shin-ichi Mizuno ◽  
Piotr Sicinski ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
B Cell ◽  
Mammalian Cells ◽  
Critical Role ◽  
Embryonic Stem ◽  
Hematopoietic Progenitors ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cyclin A2

Abstract Abstract 381 Cyclins are regulatory subunits of cyclin-dependent kinase, and are important components of cell cycle engine. The A-type cyclin is generally the S-phase cyclin. Mammalian cells express two A-type cyclins, including cyclin A1 that is exclusively expressed in the testis, and cyclin A2 whose expression is ubiquitous. We have recently reported that cyclin A2 is not required for fibroblast proliferation but it is indispensable in maintenance of self-renewal of stem cells, including embryonic stem cells and hematopoietic stem cells (HSCs) (Cell 138 2009). The question is whether cyclin A2 plays a role in proliferation of hematopoietic progenitors downstream of the HSC. Here we further assessed the requirement of A-type cyclin in non-self-renewing hematopoietic progenitors. Quantitative RT-PCR analysis showed that cyclin A2 was expressed in hematopoietic stem and progenitor cells, but its expression level is highest in lymphoid-committed progenitor stages of both T and B cell lineages. Thus, in order to test the role of cylin A2 in early lymphopoiesis, we crossed cyclin A2 floxed mice with Rag1-Cre knock-in mice. Rag1 expression is initiated at the preproB to the proB stages, and the DN1-DN3 stages in the thymus, while their proliferation is dependent at least upon pre-BCR or pre-TCR signal at these stages. Interestingly, the Rag1-Cre cyclin A2 floxed/floxed mice were viable, and have normal numbers of HSCs and myeloid progenitors in the bone marrow. They, however, displayed severe reduction of T and B cell numbers that were only 1/100 - 1/10 of wild-type controls; the number of common lymphoid progenitor was unchanged, but there were almost complete loss of proB and preB cells. Similarly, all thymic T cell progenitor compartments such as CD4-CD8- double negative, and CD4+CD8+ double positive populations were severely reduced. These findings clearly demonstrate that cyclin A2 is indispensable not only for self-renewal of HSCs, but also for proliferation of T and B cell progenitors. Disclosures: No relevant conflicts of interest to declare.

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