Sphingosine 1-phosphate Receptor Modulator ONO-4641 Regulates Trafficking of T Lymphocytes and Hematopoietic Stem Cells and Alleviates Immune-Mediated Aplastic Anemia in a Mouse Model

AbstractThpo/Mpl signaling plays an important role in the maintenance of hematopoietic stem cells (HSCs) in addition to its role in megakaryopoiesis. Patients with inactivating mutations in Mpl develop thrombocytopenia and aplastic anemia because of progressive loss of HSCs. Yet, it is unknown whether this loss of HSCs is an irreversible process. In this study, we used the Mpl knockout (Mpl−/−) mouse model and expressed Mpl from newly developed lentiviral vectors specifically in the physiologic Mpl target populations, namely, HSCs and megakaryocytes. After validating lineage-specific expression in vivo using lentiviral eGFP reporter vectors, we performed bone marrow transplantation of transduced Mpl−/− bone marrow cells into Mpl−/− mice. We show that restoration of Mpl expression from transcriptionally targeted vectors prevents lethal adverse reactions of ectopic Mpl expression, replenishes the HSC pool, restores stem cell properties, and corrects platelet production. In some mice, megakaryocyte counts were atypically high, accompanied by bone neo-formation and marrow fibrosis. Gene-corrected Mpl−/− cells had increased long-term repopulating potential, with a marked increase in lineage−Sca1+cKit+ cells and early progenitor populations in reconstituted mice. Transcriptome analysis of lineage−Sca1+cKit+ cells in Mpl-corrected mice showed functional adjustment of genes involved in HSC self-renewal.

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Correction of metachromatic leukodystrophies (MLD) in the mouse model by transplantation of genetically modified hematopoietic stem cells

Journal of the Peripheral Nervous System ◽

10.1111/j.1085-9489.2004.009209af.x ◽

2004 ◽

Vol 9 (2) ◽

pp. 113-114

Author(s):

A Quattrini ◽

A Biffi ◽

S Amadio ◽

I Bertani ◽

G Dina ◽

...

Keyword(s):

Stem Cells ◽

Mouse Model ◽

Hematopoietic Stem Cells ◽

Genetically Modified ◽

Hematopoietic Stem

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Cotransplantation of Allogeneic Mesenchymal and Hematopoietic Stem Cells in Children With Aplastic Anemia

PEDIATRICS ◽

10.1542/peds.2011-2091 ◽

2012 ◽

Vol 129 (6) ◽

pp. e1612-e1615 ◽

Cited By ~ 21

Author(s):

H. Wang ◽

H. Yan ◽

Z. Wang ◽

L. Zhu ◽

J. Liu ◽

...

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Aplastic Anemia ◽

Hematopoietic Stem

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New therapeutic approaches for protecting hematopoietic stem cells in aplastic anemia

Immunologic Research ◽

10.1007/s12026-013-8449-0 ◽

2013 ◽

Vol 57 (1-3) ◽

pp. 34-43 ◽

Cited By ~ 2

Author(s):

Wendy Weston ◽

Vineet Gupta ◽

Rebecca Adkins ◽

Roland Jurecic

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Aplastic Anemia ◽

Therapeutic Approaches ◽

Hematopoietic Stem ◽

New Therapeutic Approaches

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Faculty Opinions recommendation of Successful gene therapy of Diamond-Blackfan anemia in a mouse model and human CD34+ cord blood hematopoietic stem cells using a clinically applicable lentiviral vector.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.739368425.793582178 ◽

2021 ◽

Author(s):

Frank Staal

Keyword(s):

Stem Cells ◽

Gene Therapy ◽

Mouse Model ◽

Hematopoietic Stem Cells ◽

Cord Blood ◽

Lentiviral Vector ◽

Hematopoietic Stem ◽

Diamond Blackfan Anemia ◽

Human Cd34

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Hlf Expression Marks Early Emergence of Hematopoietic Stem Cell Precursors With Adult Repopulating Potential and Fate

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.728057 ◽

2021 ◽

Vol 9 ◽

Author(s):

Wanbo Tang ◽

Jian He ◽

Tao Huang ◽

Zhijie Bai ◽

Chaojie Wang ◽

...

Keyword(s):

Stem Cells ◽

Mouse Model ◽

Hematopoietic Stem Cells ◽

Fetal Liver ◽

Lineage Tracing ◽

Genetic Lineage ◽

Hematopoietic Stem ◽

Genetic Lineage Tracing

In the aorta-gonad-mesonephros (AGM) region of mouse embryos, pre-hematopoietic stem cells (pre-HSCs) are generated from rare and specialized hemogenic endothelial cells (HECs) via endothelial-to-hematopoietic transition, followed by maturation into bona fide hematopoietic stem cells (HSCs). As HECs also generate a lot of hematopoietic progenitors not fated to HSCs, powerful tools that are pre-HSC/HSC-specific become urgently critical. Here, using the gene knockin strategy, we firstly developed an Hlf-tdTomato reporter mouse model and detected Hlf-tdTomato expression exclusively in the hematopoietic cells including part of the immunophenotypic CD45– and CD45+ pre-HSCs in the embryonic day (E) 10.5 AGM region. By in vitro co-culture together with long-term transplantation assay stringent for HSC precursor identification, we further revealed that unlike the CD45– counterpart in which both Hlf-tdTomato-positive and negative sub-populations harbored HSC competence, the CD45+ E10.5 pre-HSCs existed exclusively in Hlf-tdTomato-positive cells. The result indicates that the cells should gain the expression of Hlf prior to or together with CD45 to give rise to functional HSCs. Furthermore, we constructed a novel Hlf-CreER mouse model and performed time-restricted genetic lineage tracing by a single dose induction at E9.5. We observed the labeling in E11.5 AGM precursors and their contribution to the immunophenotypic HSCs in fetal liver (FL). Importantly, these Hlf-labeled early cells contributed to and retained the size of the HSC pool in the bone marrow (BM), which continuously differentiated to maintain a balanced and long-term multi-lineage hematopoiesis in the adult. Therefore, we provided another valuable mouse model to specifically trace the fate of emerging HSCs during development.

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Abstract 12653: The Therapy-related Clonal Hematopoiesis Driver Gene Ppm1d Promotes Inflammation and Non-ischemic Heart Failure in a Murine Model

Circulation ◽

10.1161/circ.142.suppl_3.12653 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Yoshimitsu Yura ◽

Emiri Miura-Yura ◽

Kenneth Walsh

Keyword(s):

Stem Cells ◽

Angiotensin Ii ◽

Mouse Model ◽

Hematopoietic Stem Cells ◽

Cancer Patients ◽

Nlrp3 Inflammasome ◽

Cardiac Dysfunction ◽

Hematopoietic Stem ◽

Cardiac Stress ◽

Clonal Hematopoiesis

Background: Therapy-related clonal hematopoiesis in cancer patients is typically associated with somatic mutations in hematopoietic cell genes that encode regulators of the DNA-damage response (DDR) pathway. The Protein Phosphatase Mg2+/Mn2+ Dependent 1D ( PPM1D ) gene is the most frequently mutated DDR gene associated with therapy-related clonal hematopoiesis. While epidemiological evidence suggests an association between therapy-related clonal hematopoiesis and cardiovascular disease in cancer patients, causal and mechanistic relationships have never been evaluated in an experimental system. Methods: To test whether hematopoietic cell mutations in PPM1D can increase the susceptibility to cardiac stress, we evaluated cardiac dysfunction in response to angiotensin II infusion in a mouse model where clonal-hematopoiesis-associated mutations in Ppm1d were produced by CRISPR-Cas9 technology. Results: Mice transplanted with hematopoietic stem cells containing clinically relevant mutations in exon 6 of Ppm1d exhibited augmented cardiac remodeling following the continuous infusion of angiotensin II. Ppm1d -mutated macrophages showed impairments in the DDR pathway and had an augmented proinflammatory profile. Mice transplanted with Ppm1d mutated cells exhibited elevated IL-1β in the stressed myocardium, and bone marrow derived macrophages produced more IL-1β in response to LPS stimulation. The administration of an NLRP3 inflammasome inhibitor to mice reversed the cardiac phenotype induced by the Ppm1d -mutated hematopoietic stem cells under conditions of Angiotensin II-induced stress. Conclusions: A mouse model of Ppm1d -mediated clonal hematopoiesis was more susceptible to cardiac stress following of angiotensin II infusion. Mechanistically, disruption of the DDR pathway led to elevations in inflammatory cytokine production, and the NLRP3 inflammasome was shown to be essential for this augmented cardiac stress response. These data indicate that therapy-related clonal hematopoiesis involving mutations in PPM1D could contribute to the cardiac dysfunction observed in cancer survivors.

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Espinoza JL, Elbadry MI, Chonabayashi K, et al. Hematopoiesis by iPSC-derived hematopoietic stem cells of aplastic anemia that escape cytotoxic T-cell attack. Blood Adv. 2018;2(4):390-400.

Blood Advances ◽

10.1182/bloodadvances.2018025122 ◽

2018 ◽

Vol 2 (17) ◽

pp. 2253-2253

Keyword(s):

Stem Cells ◽

T Cell ◽

Hematopoietic Stem Cells ◽

Aplastic Anemia ◽

Cytotoxic T Cell ◽

Hematopoietic Stem

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

Blood ◽

10.1182/blood-2011-04-348904 ◽

2012 ◽

Vol 119 (3) ◽

pp. 707-716 ◽

Cited By ~ 88

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.

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