title: Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms.
abstract: Myeloproliferative neoplasms (MPNs) are diseases caused by mutations in the haematopoietic stem cell (HSC) compartment. Most MPN patients have a common acquired mutation of Janus kinase 2 (JAK2) gene in HSCs that renders this kinase constitutively active, leading to uncontrolled cell expansion. The bone marrow microenvironment might contribute to the clinical outcomes of this common event. We previously showed that bone marrow nestin(+) mesenchymal stem cells (MSCs) innervated by sympathetic nerve fibres regulate normal HSCs. Here we demonstrate that abrogation of this regulatory circuit is essential for MPN pathogenesis. Sympathetic nerve fibres, supporting Schwann cells and nestin(+) MSCs are consistently reduced in the bone marrow of MPN patients and mice expressing the human JAK2(V617F) mutation in HSCs. Unexpectedly, MSC reduction is not due to differentiation but is caused by bone marrow neural damage and Schwann cell death triggered by interleukin-1β produced by mutant HSCs. In turn, in vivo depletion of nestin(+) cells or their production of CXCL12 expanded mutant HSC number and accelerated MPN progression. In contrast, administration of neuroprotective or sympathomimetic drugs prevented mutant HSC expansion. Treatment with β3-adrenergic agonists that restored the sympathetic regulation of nestin(+) MSCs prevented the loss of these cells and blocked MPN progression by indirectly reducing the number of leukaemic stem cells. Our results demonstrate that mutant-HSC-driven niche damage critically contributes to disease manifestation in MPN and identify niche-forming MSCs and their neural regulation as promising therapeutic targets.
authors.affiliation: Stem Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Arranz
authors.affiliation: Stem Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
authors.forename: Abel
authors.initials: A
authors.lastname: Sánchez-Aguilera
authors.affiliation: Stem Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martín-Pérez
authors.affiliation: Stem Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Isern
authors.affiliation: Stem Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Langa
authors.affiliation: University Hospital Basel, CH-4031 Basel, Switzerland.
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: University Hospital Basel, CH-4031 Basel, Switzerland.
authors.forename: Pontus
authors.initials: P
authors.lastname: Lundberg
authors.affiliation: Department of Haematology, IBSAL-Hospital Universitario de Salamanca, 37007 Salamanca, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Muntión
authors.affiliation: National Taiwan University, Taipei 10002, Taiwan.
authors.forename: Yi-Shiuan
authors.initials: YS
authors.lastname: Tzeng
authors.affiliation: National Taiwan University, Taipei 10002, Taiwan.
authors.forename: Dar-Ming
authors.initials: DM
authors.lastname: Lai
authors.affiliation: University Hospital Basel, CH-4031 Basel, Switzerland.
authors.forename: Jürg
authors.initials: J
authors.lastname: Schwaller
authors.affiliation: University Hospital Basel, CH-4031 Basel, Switzerland.
authors.forename: Radek C
authors.initials: RC
authors.lastname: Skoda
authors.affiliation: Stem Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
authors.forename: Simón
authors.initials: S
authors.lastname: Méndez-Ferrer
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D053614:Janus Kinase 2 / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000473:pathology; D051379:Mice; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000473:pathology*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D009412:Nerve Fibers / Q000187:drug effects / Q000473:pathology*; D064231:Nestin / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D012583:Schwann Cells / Q000187:drug effects / Q000473:pathology; D055153:Stem Cell Niche; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D053583:Interleukin-1beta; D064231:Nestin; D018696:Neuroprotective Agents; D022702:Receptors, Adrenergic, beta-3; C507924:JAK2 protein, human; D053614:Janus Kinase 2