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.
Highlights
Protein malnutrition decreases the production of blood cells, leading to bone marrow hypoplasia and inducing structural alterations interfering with both innate and adaptive immunity [1,2,3,4]
The animals in the malnourished group consumed the same quantity of food and calories did as the controls, but their ingestion of protein was reduced because the hypoproteic diet had a lower protein content
This study indicates that protein malnutrition induced central and peripheral leukopenia, and these results are, in part, due to a hematopoiesis compromise resulting from changes in the hematopoietic cells as well as in the bone marrow mesenchymal stem cells (MSCs)
Summary
Protein malnutrition decreases the production of blood cells, leading to bone marrow hypoplasia and inducing structural alterations interfering with both innate and adaptive immunity [1,2,3,4]. Blood cells arise in the bone marrow from stem cells able to undergo processes of proliferation and differentiation in the hematopoietic microenvironment [5,6]. The cellular constituents of the bone marrow microenvironment, defined as the hemopoietic niche, largely derive from a common progenitor of mesenchymal origin called mesenchymal stem cells (MSCs), initially identified in adult bone marrow and that have classically the ability to self-renew and differentiate into tissues of mesodermal origin such as osteocytes, chondrocytes and adipocytes [6,7]. The bone marrow adipocyte is one type of cell that currently has been paid more attention for being able to modulate hematopoiesis and that is not just a type of tissue filler [8,9]. The literature reports on the importance of the bone marrow adipocytes in complex hematopoietic regulation and on the influence of bone marrow adipocytes as negative regulators of hematopoiesis compromising the capacity to produce growth factors such as granulocyte-macrophage colony stimulator factor (GM-CSF) and granulocyte colony stimulator factor (G-CSF) [8]
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