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Systemic Dysfunction of Osteoblast Differentiation in Adipose-Derived Stem Cells from Patients with Multiple Myeloma

1
INSERM, UMR_S 938, Centre de Recherche Saint-Antoine-Team Genetic and Acquired Lipodystrophies, Institut Hospitalo-Universitaire de Cardiométabolisme et Nutrition (ICAN), Sorbonne Université, F-75012 Paris, France
2
INSERM, UMR_S 938, Centre de Recherche Saint-Antoine-Team Proliferation and Differentiation of Stem Cells, Institut Universitaire de Cancérologie, Sorbonne Université, F-75012 Paris, France
3
EFS Ile de France, Unité d’Ingénierie et de Thérapie Cellulaire, F-94017 Créteil, France
4
INSERM, CNRS, UMR_S 938, Centre de Recherche Saint-Antoine- Team Cancer Biology and Therapeutics, Institut Universitaire de Cancérologie, Sorbonne Université, F-75012 Paris, France
5
INSERM, UMR_S 938, Centre de Recherche Saint-Antoine-Team Proliferation and Differentiation of Stem Cells, Institut Universitaire de Cancérologie, Sorbonne Université, F-75012 Paris, France
6
INSERM, UMR_S 938, Centre de Recherche Saint-Antoine-Team Genetic and Acquired Lipodystrophies, Institut Hospitalo-Universitaire de Cardiométabolisme et Nutrition (ICAN), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, service d’Endocrinologie, Sorbonne Université, F-75012 Paris, France
7
INSERM, UMR_S 938, Centre de Recherche Saint-Antoine-Team Proliferation and Differentiation of Stem Cells, Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine, Département d’Hématologie et de Thérapie Cellulaire, Sorbonne Université, F-75012 Paris, France
*
Author to whom correspondence should be addressed.
These authors contributed equally to this paper.
These authors contributed equally to this paper.
Cells 2019, 8(5), 441; https://doi.org/10.3390/cells8050441
Received: 28 March 2019 / Revised: 29 April 2019 / Accepted: 8 May 2019 / Published: 10 May 2019
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Multiple Myeloma)
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Abstract

Multiple myeloma is characterized by bone lesions linked to increased osteoclast and decreased osteoblast activities. In particular, the osteoblast differentiation of bone marrow-derived stem cells (MSC) is impaired. Among the potential therapeutic tools for counteracting bone lesions, adipose-derived stem cells (ASC) could represent an appealing source for regenerative medicine due to their similar characteristics with MSC. Our study is among the first giving detailed insights into the osteoblastogenic capacities of ASC isolated by fat aspiration from myeloma patients (MM-ASC) compared to healthy subjects (HD-ASC). We showed that MM-ASC and HD-ASC exhibited comparable morphology, proliferative capacity, and immunophenotype. Unexpectedly, although normal in adipocyte differentiation, MM-ASC present a defective osteoblast differentiation, as indicated by less calcium deposition, decreased alkaline phosphatase activity, and downregulation of RUNX2 and osteocalcin. Furthermore, these ASC-derived osteoblasts displayed enhanced senescence, as shown by an increased β-galactosidase activity and cell cycle inhibitors expression (p16INK4A, p21WAF1/CIP1.), associated with a markedly increased expression of DKK1, a major inhibitor of osteoblastogenesis in multiple myeloma. Interestingly, inhibition of DKK1 attenuated senescence and rescued osteoblast differentiation, highlighting its key role. Our findings show, for the first time, that multiple myeloma is a systemic disease and suggest that ASC from patients would be unsuitable for tissue engineering designed to treat myeloma-associated bone disease.
Keywords: multiple myeloma; bone disease; osteogenesis; adipogenesis; adipose-derived stem cells; bone marrow; senescence; Dickkopf-related protein 1; systemic disease multiple myeloma; bone disease; osteogenesis; adipogenesis; adipose-derived stem cells; bone marrow; senescence; Dickkopf-related protein 1; systemic disease
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Béréziat, V.; Mazurier, C.; Auclair, M.; Ferrand, N.; Jolly, S.; Marie, T.; Kobari, L.; Toillon, I.; Delhommeau, F.; Fève, B.; Larsen, A.K.; Sabbah, M.; Garderet, L. Systemic Dysfunction of Osteoblast Differentiation in Adipose-Derived Stem Cells from Patients with Multiple Myeloma. Cells 2019, 8, 441.

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