Heterogeneity of the bone marrow niche in patients with myeloproliferative neoplasms: ActivinA secretion by mesenchymal
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ORIGINAL ARTICLE
Heterogeneity of the bone marrow niche in patients with myeloproliferative neoplasms: ActivinA secretion by mesenchymal stromal cells correlates with the degree of marrow fibrosis Benedetta Rambaldi 1,2,3 & Elisa Diral 1,2,4 & Samantha Donsante 5 & Noemi Di Marzo 1 & Federica Mottadelli 1 & Lucia Cardinale 1 & Erica Dander 1 & Giuseppe Isimbaldi 6,7 & Pietro Pioltelli 2 & Andrea Biondi 8 & Mara Riminucci 5 & Giovanna D’Amico 1 & Elena Maria Elli 2 & Alice Pievani 1 & Marta Serafini 1 Received: 25 May 2020 / Accepted: 15 October 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Mesenchymal stromal cells (MSCs) represent an essential component of the bone marrow (BM) niche and display disease-specific alterations in several myeloid malignancies. The aim of this work was to study possible MSC abnormalities in Philadelphia-negative myeloproliferative neoplasms (MPNs) in relationship to the degree of BM fibrosis. MSCs were isolated from BM of 6 healthy donors (HD) and of 23 MPN patients, classified in 3 groups according to the diagnosis and the grade of BM fibrosis: polycythemia vera and essential thrombocythemia (PV/ET), low fibrosis myelofibrosis (LF-MF), and high fibrosis MF (HF-MF). MSC cultures were established from 21 of 23 MPN patients. MPN-derived MSCs did not exhibit any functional impairment in their adipogenic/ osteogenic/chondrogenic differentiation potential and displayed a phenotype similar to HD-derived MSCs but with a decreased expression of CD146. All MPN-MSC lines were negative for the patient-specific hematopoietic clone mutations (JAK2, MPL, CALR). MSCs derived from HF-MF patients displayed a reduced clonogenic potential and a lower growth kinetic compared to MSCs from HD, LF-MF, and PV/ET patients. mRNA levels of hematopoiesis regulatory molecules were unaffected in MSCs from HF-MF compared to HD. Finally, in vitro ActivinA secretion by MSCs was increased in HF-MF compared to LF-MF patients, in association with a lower hemoglobin value. Increased ActivinA immunolabeling on stromal cells and erythroid precursors was also observed in HF-MF BM biopsies. In conclusion, higher grade of BM fibrosis is associated with functional impairment of MSCs and the increased secretion of ActivinA may represent a suitable target for anemia treatment in MF patients. Keywords Myeloproliferative neoplasms . Myelofibrosis . Mesenchymal stromal cells . ActivinA Elena Maria Elli, Alice Pievani, and Marta Serafini share senior authorship. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00277-020-04306-w) contains supplementary material, which is available to authorized users. * Elena Maria Elli [email protected]
4
Hematology Department, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
* Marta Serafini [email protected]
5
Department of Molecular Medicine, Sapienza University, Rome, Italy
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Department of Pathology, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
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Department of Pathology, ASST G
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