title: Protein malnutrition induces bone marrow mesenchymal stem cells commitment to adipogenic differentiation leading to hematopoietic failure.
abstract: Protein malnutrition (PM) results in pathological changes that are associated with peripheral leukopenia, bone marrow (BM) hypoplasia and alterations in the BM microenvironment leading to hematopoietic failure; however, the mechanisms involved are poorly understood. In this context, the BM mesenchymal stem cells (MSCs) are cells intimately related to the formation of the BM microenvironment, and their differentiation into adipocytes is important because adipocytes are cells that have the capability to negatively modulate hematopoiesis. Two-month-old male Balb/c mice were subjected to protein-energy malnutrition with a low-protein diet containing 2% protein, whereas control animals were fed a diet containing 12% protein. The hematopoietic parameters and the expression of CD45 and CD117 positive cells in the BM were evaluated. MSCs were isolated from BM, and their capability to produce SCF, IL-3, G-CSF and GM-CSF were analyzed. The expression of PPAR-γ and C/EBP-α as well as the expression of PPAR-γ and SREBP mRNAs were evaluated in MSCs together with their capability to differentiate into adipocytes in vitro. The malnourished animals had anemia and leukopenia as well as spleen and bone marrow hypoplasia and a reduction in the expression of CD45 and CD117 positive cells from BM. The MSCs of the malnourished mice presented an increased capability to produce SCF and reduced production of G-CSF and GM-CSF. The MSCs from the malnourished animals showed increased expression of PPAR-γ protein and PPAR-γ mRNA associated with an increased capability to differentiate into adipocytes. The alterations found in the malnourished animals allowed us to conclude that malnutrition committed MSC differentiation leading to adipocyte decision and compromised their capacity for cytokine production, contributing to an impaired hematopoietic microenvironment and inducing the bone marrow failure commonly observed in protein malnutrition states.
authors.affiliation: Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Mayara Caldas Ramos
authors.initials: MC
authors.lastname: Cunha
authors.forename: Fabiana da Silva
authors.initials: Fda S
authors.lastname: Lima
authors.forename: Marco Aurélio Ramirez
authors.initials: MA
authors.lastname: Vinolo
authors.forename: Araceli
authors.initials: A
authors.lastname: Hastreiter
authors.forename: Rui
authors.initials: R
authors.lastname: Curi
authors.forename: Primavera
authors.initials: P
authors.lastname: Borelli
authors.forename: Ricardo Ambrósio
authors.initials: RA
authors.lastname: Fock
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D050156:Adipogenesis; D000818:Animals; D001835:Body Weight; D001854:Bone Marrow Cells / Q000473:pathology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D004032:Diet; D004044:Dietary Proteins / Q000378:metabolism; D004435:Eating; D005347:Fibroblasts / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006410:Hematopoiesis; D007377:Interleukin-3 / Q000096:biosynthesis; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011502:Protein-Energy Malnutrition / Q000378:metabolism* / Q000473:pathology*; D012709:Serum Albumin / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004044:Dietary Proteins; D007377:Interleukin-3; D047495:PPAR gamma; D012709:Serum Albumin; D051779:Sterol Regulatory Element Binding Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor