Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms
Open accessAbstract
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.
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In murine models of MPN and AML, the hematological malignancy created neuropathic changes in the BM niche, which affected the activity of MSCs and altered the function of the HSC niche, leading to downregulated expression of many HSC-retention factors, including CXCL12 and SCF.
“In murine models of MPN 80 and AML, 81 the hematological malignancy created neuropathic changes in the BM niche, which affected the activity of MSCs and altered the function of the HSC niche, in particular leading to downregulated expression of many HSC-retention factors, including CXCL12 and SCF, indicating loss of hematopoiesis support.”
From Inflammatory bone marrow microenvironment (2019) · cites this paper as [80]
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Self-citation
- Authors
- Arranz, L., Sánchez-Aguilera, A., Martín-Pérez, D., Isern, J., Langa, X., Tzankov, A., Lundberg, P., Muntión, S., Tzeng, Y.-S., Lai, D.-M., Schwaller, J., Skoda, R. C., & Méndez-Ferrer, S.
- Affiliations
- Spanish National Centre for Cardiovascular Research (ES)
- University Hospital of Basel (CH)
- Instituto de Investigación Biomédica de Salamanca (ES)
- National Taiwan University (TW)
- ORCID
- Venue
- Nature
- Published
- 2014-06-22
- Volume
- 512
- Issue
- 7512
- Pages
- 78-81
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2045032252
- Cited by
- 444
- References
- 36
- Citations by year
- 2026: 13 · 2025: 22 · 2024: 29 · 2023: 36 · 2022: 38 · 2021: 49 · 2020: 50 · 2019: 43 · 2018: 40 · 2017: 45 · 2016: 31 · 2015: 35 · 2014: 13
- FWCI
- 20.74
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- edoc (University of Basel) (submittedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by-nc-nd)
- Funders
- Howard Hughes Medical Institute
- Topics
- Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- myeloproliferative neoplasms, bone marrow microenvironment, mesenchymal stem cells, sympathetic innervation, JAK2 V617F mutation, nestin, Schwann cells, IL-1β, CXCL12, beta3-adrenergic agonists, neuroprotective agents
- MeSH terms
- Animals, Female, Hematopoietic Stem Cells, Humans, Myeloproliferative Disorders, Neoplasms, Nerve Fibers, Schwann Cells, Sympathetic Nervous System, Neoplastic Stem Cells, Apoptosis, Disease Progression, Neuroprotective Agents, Receptors, Adrenergic, beta-3, Mice, Interleukin-1beta, Janus Kinase 2, Stem Cell Niche, Adrenergic beta-3 Receptor Agonists, Mesenchymal Stem Cells, Nestin
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