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Honorary Professor Jean-Pierre Levesque

PhD, BSc

Professorial Research Fellow

Projects

Mechanisms and treatments of heterotopic ossification following spinal cord and brain injuries

A frequent complication of traumatic brain and spinal cord injuries is the formation of extra bones in muscles called neurogenic heterotopic ossifications. These extra bones develop around the joints in the weeks after a neurological injury to become so large that they stop joint movement, resulting in increased disability and pain. This project is aims to understand why these bones develop after spinal cord injury and to discover new effective treatments to prevent their development.

Mechanisms of anaemia associated with inflammatory bowel diseases

Inflammatory bowel diseases (IBD) affect 0.6% Australians (≈160,000). The most common complication of IBD is anaemia (low levels haemoglobin and red blood cells). This anaemia causes high morbidity with persistent fatigue, cardiac insufficiency, and early death due to insufficient body oxygenation. Anaemic patients are treated by iron supplementation but it is not effective. This Ideas grant is to understand the mechanisms that cause anaemia in IBD and find better treatments to correct it.

Discovery of new niche regulators of haematopoietic stem cells

About me

A/Prof Jean-Pierre Levesque is a NHMRC Senior Research Fellow. He is co-head the Blood and Bone Diseases Program and head of the Stem Cell Biology Group at Mater Research Institute- University of Queensland. His major research interest is to understand how the bone marrow microenvironment regulates the fate of haematopoietic and leukaemia stem cells. His is also interested in the cross-regulations between the haematopoietic, immune, bone and nervous systems. His major contributions include the discovery of many of the mechanisms responsible for the mobilisation of haematopoietic stem cells into the blood. He was the first to identify the role of hypoxia, macrophages and endothelial selectins as critical regulators of haematopoietic stem cells in their bone marrow niches. His interest in the abnormal differentiation of adult somatic stem cells has led him to investigate the mechanisms of heterotopic ossification following spinal cord injuries. His group has created the first mouse model of this frequent complication of spinal cord injuries.

 

 

Publications

  1. Girard D, Tseng HW, Rival B, Barbier V, Shatunova S, Goriot ME, Samuel SG, Genet F, Salga M, Banzet S, Alexander KA, Lévesque JP. Interleukin-6 does not contribute to neurogenic heterotopic ossification pathogenesis. 2024 Neurotrauma Reports, in press.
  2. Sims NA, Levesque JP. Oncostatin M a dual regulator of the skeletal and hematopoietic systems. 2024 Current Osteoporosis Reports 22: 80-95. DOI: 10.1007/s11914-023-00837-z
  3. Lineburg KE, Leveque-El Mouttie L, Hunter CR, Le Texier L, McGirr C, Teal B, Blazar BR, Lane SW, Hill GR, Levesque JP, MacDonald KPA. Autophagy prevents graft failure during GVHD. 2024 Blood Advances 8(8): 2032-2043. DOI: 10.1182/bloodadvances.2023010972 [See Inside Blood Advances: “Better eat!” by Nelson Chao, pp2030-2031
  4. Salga M, Samuel DG, Tseng HW, Gatin L, Girard D, Rival B, Bisht K, Shatunova S, Debaud C, Winkler IG, Paquereau J, Dinh A, Genet G, Kerever S, Abback PS, Banzet S, Genet F, Lévesque JP, Alexander KA. Bacterial lipopolysaccharides exacerbate neurogenic heterotopic ossification development. 2023 J Bone Miner Res 38(11): 1700-1717, DOI: 10.1002/jbmr.4905
  5. Foo CX, Bartlett S, Chew KY, Ngo MD, Bielefedt-Ohmann H, Arachchige BJ, Mathhews B, Reed S, Wang R, Smith C, Sweet MJ, Burr L, Bisht K, Shatunova S, Sinclair JE, Parry R, Yang Y, Lévesque JP, Kromykh A, Rosenkilde MM, Short KR, Ronacher K. GPR183 antagonism reduces macrophage infiltration in influenza and SARS-CoV-2 infection. 2023 Eur Respir J 61(3): 2201306. DOI: 10.1183/13993003.01306-2022
  6. Tay J, Bisht K, Winkler IG, Levesque JP. Imagining flow cytometry analysis of primary bone marrow erythroblastic islands. 2023 Methods Mol Biol 635: 43-61. DOI: 10.1007/978-1-0716-3020-4_3
  7. Tseng HW, Samuel SG, Schroder K, Levesque JP, Alexander KA. Inflammasomes and the IL-1 family in bone homeostasis and disease. 2022 Current Osteoporosis Reports 20(3):170-185. DOI: 10.1007/s11914-022-00729-8.
  8. Tseng HW, Girard D, Millard SM, Alexander KA, Torossian F, Anginot A, Fleming A, Gueguen J, Goriot ME, Clay D, Jose B, Nowlan B, Pettit AR, Salga M, Genêt F, Le Bousse-Kerdilès MC, Banzet S, Levesque JP. Spinal cord injury reprograms muscle fibro-adipogenic progenitors to form heterotopic bones within muscles. 2022 Bone Research 10(1): 22. DOI: 10.1038/s41413-022-00188-y
  9. Tseng HW, Kulina I, Girard D, Gueguen J, Vaquette C, Salga M, Fleming W, Jose B, Millard SM, Pettit AR, Schroder K, Thomas G, Wheeler L, Genêt F, Banzet S, Alexander KA, Levesque JP. Interleukin-1 is overexpressed in injured muscles following spinal cord injury and promotes neurogenic heterotopic ossification. 2022 J Bone Miner Res 37(3): 531-546. DOI: 10.1002/jbmr.4482
  10. Bisht K, McGirr C, Lee SY, Tseng HW, Fleming F, Alexander KA, Matsumoto T, Barbier V, Sims NA, Müller-Newen G, Winkler IG, Bönig H, Levesque JP. Oncostatin M regulates hematopoietic stem cell (HSC) niches in the bone marrow to restrict HSC mobilization. 2021 Leukemia 36(2): 333-347. DOI: 10.1038/s41375-021-01413-z
  11. Alexander KA, Tseng HW, Kulina I, Fleming W, Vaquette C, Genêt F, Ruitenberg MJ, Levesque JP. Lymphocytes are not required for neurogenic heterotopic ossification development after spinal cord injury. 2022 Neurotrauma Reports 3(1):87-96. DOI: 10.1089/neur.2021.0072.
  12. Millard SM, Heng O, Opperman KS, Sehgal A, Irvine KM, Kaur S, Sandrock CJ, Wu AC, Magor GW, Batoon L, Perkins AC, Noll JE, Zannettino ACW, Sester DP, Levesque JP, Raggatt LJ, Summers KM, Pettit AR. Fragmentation of tissue-resident macrophages during isolation confounds analysis of single cell preparations from mouse hematopoietic tissue. 2021 Cell Rep 37(8): 110058. DOI: 10.1016/j.celrep.2021.110058.
  13. Levesque JP, Summers KM, Bisht K, Millard S, Winkler IG, Pettit AR. Macrophages form erythropoietic niches and regulate iron homeostasis in response to infections and inflammation. 2021 Exp Hematol 103: 1-14.. DOI: 10.1016/j.exphem.2021.08.011
  14. Tay J, Helwani FM, Price G, Barbier V, Levesque JP, Winkler IG. Prostacyclin is an endosteal bone marrow niche component and its clinical analog iloprost protects hematopoietic stem cell potential during stress. 2021 STEM Cells 39(11):1532-1545. DOI: 10.1002/stem.3438
  15. Levesque JP, Summers KM, Millard S, Bisht K, Winkler IG, Pettit AR. Role of macrophages and phagocytes in orchestrating normal and pathological haematopoietic niches. 2021 Exp Hematol 100: 12-31. DOI: 10.1016/j.exphem.2021.07.001
  16. Debaud C, Tseng HW, Chedik M, Kulina I, Genet F, Ruitenberg MJ, Levesque JP. Local and systemic factors drive ectopic osteogenesis in regenerating muscles of spinal cord-injured mice in a lesion level-dependent manner.2021. J Neurotrauma 38(15): 2162-2175. DOI: 10.1089/neu.2021.0058
  17. Davies JM; Radford KJ; Begun J; Levesque JP, Winkler IG. Adhesion to E-selectin primes macrophages for activation through AKT and mTOR. 2021. Immunol Cell Biol 99: 622-639. DOI: 10.1111/imcb.12447
  18. Starobova H, Monteleone M, Adolphe C, Batoon L, Sandrock CJ, Tay B, Deuis JR, Smith AV, Mueller A, Nadar EI, Pamo Lawrence G, Mayor A, Tolson E, Levesque JP, Pettit AR, Wainwright B, Schroder K, Vetter I. Vincristine-induced peripheral neuropathy is driven by canonical NLRP3 activation and IL-1β release. 2021 J Exp Med 218(5): e20201452. DOI: 10.1084/jem.20201452
  19. Girard D, Torossian F, Oberlin E, Alexander KA, Gueguen J, Tseng HW, Genêt F, Lataillade JJ, Salga M, Levesque JP, Le Bousse-Kerdilès MC, Banzet S. Neurogenic heterotopic ossifications recapitulate hematopoietic stem cell niche development within an adult osteogenic muscle environment. 2021 Front Cell Dev Biol 9: Article 611842. DOI: 10.3389/fcell.2021.611842
  20. Tay J, Bisht K, McGirr C, Millard S, Pettit AR, Winkler IG, Levesque JP. Imaging flow cytometry reveals that G-CSF causes loss of erythroblastic islands in the mouse bone marrow. 2020 Exp Hematol 82(2): 33-42. DOI: 10.1016/j.exphem.2020.02.003
  21. Barbier V, Erbani J, Fiveash C, Tallack MR, Tay J, Davies JM, Lowe J, Magnani JL, Pattabiraman, DR, Perkins AC, Lisle J, Rasko JEJ, Levesque JP, Winkler IG. Endothelial E-selectin improves acute myeloid leukaemia therapy by disrupting vascular niche-mediated chemoresistance. 2020 Nature Communications 11(1): 2042. DOI: 10.1038/s41467-020-15817-5
  22. Erbani J, Tay J, Barbier V, Levesque JP, Winkler IG. Acute myeloid leukemia chemo-resistance is mediated by E-selectin receptor CD162 in bone marrow niches. 2020 Front Cell Dev Biol 8: Article 668. DOI: 10.3389/fcell.2020.00668
  23. Tseng HW, Kulina, I, Salga M, Fleming W, Vaquette C, Genet F, Levesque JP, Alexander KA. Neurogenic heterotopic ossification develops independently of granulocyte-colony stimulating factor and neutrophils. 2020 J Bone Miner Res 35(11): 2242-2251. DOI: 10.1002/jbmr.4118
  24. Bisht K, Tay J, Wellburn RN, McGirr C, Fleming W, Nowlan B, Barbier V, Winkler IG, Levesque JP. Bacterial polysaccharides suppress medullary erythroblastic islands and erythropoiesis in the bone marrow. 2020 Front Immunol 11: Article 583550. DOI: 10.3389/fimmu.2020.583550
  25. Alexander KA, Tseng HW, Salga M, Genet F, Levesque JP. When the nervous system turns skeletal muscles into bones: How to solve the conundrum of neurogenic heterotopic ossification. 2020 Current Osteoporosis Reports 18: 666-676. DOI: 10.1007/s11914-020-00636-w
  26. Alexander KA, Tseng HW, Fleming W, Jose B, Salga M, Kulina I, Millard SM, Pettit AR, Genet F, Levesque JP. Inhibition of JAK1/2 Tyrosine kinases reduces neurogenic heterotopic ossification after spinal cord injury.2019 Front Immunol 10: 377. DOI: 10.3389/fimmu.2019.00377
  27. Bisht K, Brunck ME, Matsumoto T, McGirr C, Nowlan B, Keechy, T, Magor G, Perkins A, Davies J, Walkinshaw G, Flippin L, Winkler IG, Levesque JP. HIF prolyl hydroxylase inhibitor FG-4497 enhances mouse hematopoietic stem cell mobilization via VEGFR2/KDR. 2019 Blood Advances 3(3):406-418.
  28. Salga M, Tseng HW, Alexander KA, Jose B, Vaquette C, Haigh O, Debaud C, Gatin L, Genêt F, Levesque JP. Blocking neuromuscular junctions to impair muscle hypertonia enhances neurological heterotopic ossifications (NHO) development in a mouse model of spinal cord injury.2019 Annals of Physical and Rehabilitation Medicine 62(3):189-192.
  29. Kaur S, Raggatt LJ, Sunderland C, Millard S, Wu AC, Batoon L, Jacobsen RN, Winkler IG, MacDonald KP, Perkins AC, Hume DA, Levesque JP, Pettit AR. Self-repopulating recipient bone marrow resident macrophages promote hematopoietic stem cell engraftment. 2018 Blood 132(7):735-749.
  30. Levesque JP, Sims NA, Pettit AR, Alexander K, Tseng HW, Torossian F, Genet F, Lataillade JJ, Le Bousse-Kerdiles MC. Macrophages driving heterotopic ossification: Convergence of genetically-driven and trauma-driven mechanisms. 2018 J Bone Miner Res 33(2):365-366.
  31. Torossian F, Guerton B, Anginot A, Alexander KA, Desterke C, Soave S, Tseng HW, Arouche N, Boutin L, Kulina I, Salga M, Je B, Pettit AR, Clay D, Rochet N, Vlachos E, Genet G, Debaud C, Denormandie P, Genet F, Sims NA, Banzet S, Levesque JP, Lataillade JJ, Le Bousse-Kerdiles MC. Macrophage-derived oncostatin M contributes to human and mouse neurogenic heterotopic ossifications. 2017 JCI Insight 2(11):e96034.
  32. Debaud C, Salga M, Begot L, Holy X, de l’Escalopier N, Torossian F, Chedik M, Levesque JP, Lataillade JJ, le Bousse-Kerdiles MC, Genet F. Peripheral denervation participates in heterotopic ossification in a spinal cord injury model. 2017 PLoS One 12(8): e0182454.
  33. Nowlan B, Futrega K, Brunck ME, Walkinshaw G, Flippin LE, Doran MR, Levesque JP. HIF-1a stabilizing agent FG-4997 rescues human CD34+ cell mobilization in response to G-CSF in immuno-deficient mice. 2017 Exp Hematol 52(8): 50-55.
  34. Tay J, Levesque JP, Winkler IG. Cellular players of hematopoietic stem cell mobilization in the bone marrow niche. 2017 Int J Hematol 105(2): 129-140.
  35. Kaur S, Raggatt LJ, Batoon L, Hume DA, Levesque JP, Pettit AR. Role of bone marrow macrophages in controlling homeostasis and repair in bone and bone marrow niches. 2017 Semin Cell Dev Biol 61: 12-21.
  36. Levesque JP, Winkler IG. Cell adhesion molecules in normal and malignant hematopoiesis: from bench to bedside. Curr Stem Cell Rep 2016; 2(4):356-367.
  37. Winkler IG, Wiercinska E, Barbier V, Nowlan B, Bonig H, Levesque JP. Mobilization of hematopoietic stem cells with highest self-renewal by G-CSF precedes clonogenic cell mobilization peak. 2016 Exp Hematol 44(4): 303-314.
  38. Jacobsen RN, Nowlan B, Brunck ME, Barbier V, Winkler IG, Levesque JP. Fms-like tyrosine kinase-3 (Flt3) ligand depletes erythroid island macrophages and blocks medullar erythropoiesis in the mouse. 2016 Exp Hematol 44(3): 207-212.
  39. Holzapfel BM, Hutmacher DW, Nowlan B, Barbier V, Thibaudeau L, Theodoropoulos C, Hutmacher CO, Hooper JD, Loessner D, Clements JA, Russell PJ, Pettit AR, Winkler IG, Levesque JP. Tissue engineered humanized bone supports human hematopoiesis in vivo. 2015 Biomaterials 61: 103-114.
  40. Forristal CE, Brown AL, Helwani FM, Winkler IG, Nowlan B, Barbier V, Powell J, Engler GA, Diakiw SM, Zannettino ACW, Martin S, Pattabiraman D, D’Andrea RJ, Lewis ID, Levesque JP. Hypoxia Inducible Factor (HIF)-2α accelerates disease progression in mouse models of leukemia and lymphoma but is not a poor prognosis factor in human AML. 2015 Leukemia 29(10): 2075-208
  41. Genêt F, Kulina I, Vaquette C, Torossian F, Millard S, Pettit AR, Sims NA, Anginot A, Guerton B, Winkler IG, Barbier V, Lataillade JJ, Le Bousse-Kerdilès MC, Hutmacher DW, Levesque JP. Neurological heterotopic ossification following spinal cord injury is triggered by macrophage-mediated inflammation in muscle. 2015 J Pathol 236(2): 229-240.
  42. Jacobsen RN, Perkins AC, Levesque JP. Macrophages and regulation of erythropoiesis. 2015 Curr Opin Hematol 22(3): 212-219.
  43. Forristal CE, Nowlan B, Jacobsen RN, Barbier V, Walkinshaw G, Walkley CR, Winkler IG, Levesque JP. HIF-1α is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1α. 2015 Leukemia 29(6): 1366-1378.
  44. Jacobsen RN, Forristal CE, Raggatt LJ, Nowlan B, Barbier V, Kaur S, van Rooijen N, Winkler IG, Pettit AR, Levesque JP. Mobilization with granulocyte colony-stimulating factor blocks medullar erythropoiesis by depleting F4/80+VCAM1+CD169+ER-HR3+Ly6G+ erythroid island macrophages in the mouse. 2014 Exp Hematol 42(7): 547-561.e4.
  45. Pattabiraman DR, McGirr C, Shakhbazov K, Barbier V, Krishnan K, Mukhopadhyay P, Hawthorne P, Trezise AEO, Ding J, Grimmond SM, Papathanasiou P, Alexander WS, Perkins AC, Levesque JP, Winkler IG,Gonda TJ. Interaction of c-Myb with p300 is required for the induction of acute myeloid leukemia (AML) by human AML oncogenes. 2014 Blood 123(17); 2682-2690.
  46. Forristal CE, Levesque JP. Targeting the hypoxia sensing pathway in clinical hematology. 2014 Stem Cells Translation Medicine 3(2): 135-140.
  47. Levesque JP, Winkler IG, Rasko JEJ. Nichotherapy for stem cells: There goes the neighbourhood. 2013 BioEssays 35(3), 183-190.
  48. Winkler IG, Bendall LJ, Helwani F, Forristal CE, Nowlan B, Barbier V, Shen Y, Cisterne A, Sedger LM, Levesque JP. B-lymphopoiesis is stopped by mobilizing doses of G-CSF and is rescued by overexpression of the anti-apoptotic protein Bcl2. 2013 Haematologica 98(3), 325-333.
  49. Forristal CE, Winkler IG, Nowlan B, Barbier V, Walkinshaw G, Levesque JP. Pharmacological stabilization of the oxygen-labile transcription factor HIF-1α increases hematopoietic stem cell quiescence and accelerates blood recovery following irradiation. 2013 Blood 121(5), 759-769.
  50. Winkler IG, Barbier V, Nowlan B, Jacobsen RN, Forristal CE, Patton JT, Magnani JL, Levesque JP. Vascular E-selectin regulates hematopoietic stem cell dormancy, self-renewal and chemoresistance. 2012 Nature Medicine 18(11), 1651-1657. [See News and Views: “Waking up HSCs: a new role for E-selectin” by Moore MAS, pp1613-1614].
  51. Barbier V, Winkler IG, Levesque JP. Mobilization of hematopoietic stem cells by depleting bone marrow macrophages. 2012 Methods Mol Biol 904, 117-138.
  52. Levesque JP. N(o)-cadherin role for hematopoietic stem cells. 2012 Blood 120(2), 237-238.
  53. Winkler IG, Pettit AR, Raggatt LJ, Jacobsen R, Barbier V, Nowlan B, Cisterne A, Bendall LJ, Sims NA, Lévesque JP. Hematopoietic stem cell (HSC) mobilizing agents G-CSF, cyclophosphamide or AMD3100 have distinct mechanisms of action on bone marrow HSC niches and bone formation. 2012 Leukemia 26(7), 1594-1601.
  54. Barbier V, Winkler IG, Wadley R, Levesque JP. Flow Cytometry measurement of bone marrow perfusion in the mouse and sorting of progenitors and stems cells according to position relative to blood flow in vivo. 2012 Methods Mol Biol 844, 45-63.
  55. Barbier V, Nowlan B, Levesque JP, Winkler IG. Flow cytometry analysis of cell cycling and proliferation in mouse hematopoietic stem and progenitor cells. 2012 Methods Mol Biol, 844, 31-44.
  56. To LB, Levesque JP, Herbert KE. How I treat patients who mobilize hematopoietic stem cells poorly. 2011 Blood 118(17), 4530-4540.
  57. To LB, Levesque JP, Herbert KE, Winkler IG, Bendall LJ, Hiwase D, Antonenas V, Rice A, Gottlieb DJ, Mills AK, Rasko JE, Larsen SR, Beligaswatte A, Nilsson SK, Cooney J, Cambareri T, Lewis I. Mobilisation strategies for normal and malignant cells. 2011 Pathology 43(6), 547-565.
  58. Herbert KE, Lévesque JP, Mills AK, Gottlieb DJ, Cooney J, Szer J, Rasko J, To LB. How we mobilise haemopoietic stem cells? 2011 Intern Med J 41(8):588-594.
  59. Lévesque JP, Winkler IG. Hierarchy of immature hematopoietic cells related to blood flow and niche. 2011 Curr Opin Hematol 18(4), 220-225.
  60. Levesque JP, Helwani FM, Winkler IG. The “osteoblastic” niche and its role in hematopoietic stem cell homing and mobilization. 2010 Leukemia 24(12), 1979–1992.
  61. Winkler IG, Sims MA, Pettit AR, Barbier V, Nowlan B, Helwani F, Poulton IJ, van Rooijen N, Alexander KA, Raggatt LJ, Levesque JP. Bone marrow macrophages are essential to hematopoietic stem cell (HSC) niches and their depletion mobilizes HSC. 2010 Blood 116(23), 4815-4828.
  62. Shen Y, Winkler IG, Barbier V, Sims NA, Hendy J, Levesque JP. Tissue inhibitor of metalloproteinase-3 (TIMP-3) regulates hematopoiesis and bone formation in vivo. 2010 PLoS One 5, e13086.
  63. Winkler IG, Barbier V, Wadley R, Zannettino A, Williams S, Levesque JP. Positioning of bone marrow hematopoietic and stromal cells relative to blood flow in vivo: Serially reconstituting hematopoietic stem cells reside in distinct non-perfused niches. 2010 Blood 116(3), 375-385. [see Editorial commentary: “Stem cells hold their breath” by Adams GA pp307-308”.]

 

Events / Articles

NEWS & MEDIA
 
PROMISING NEW DRUG FOR ACUTE MYELOID LEUKAEMIA
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2017 NHMRC GRANTS ANNOUNCED
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2015 NHMRC GRANTS ANNOUNCED
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Research fields

Haematology, Stem Cell Biology, Stem Cell Niche, Bone marrow transplantation, Leukaemia, Heterotopic Ossification

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