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.

The influence of protein malnutrition on the production of GM-CSF and M-CSF by macrophages

“…Based on previous literature results (Vinolo et al, 2008;Cunha et al, 2013;Oliveira et al, 2014) and with the current results, we can conclude that PM impacts GM-CSF production, leading to alterations in hematopoietic cell production and immune response. This pattern of cytokine production could partially explain immunodeficiency and the hematopoietic changes presented in proteinmalnourished organisms.…”

“…which malnutrition is not associated with other diseases, leukopenia always occurs (Catchatourian et al, 1980;Grimble, 1996;Borelli et al, 2009;Cunha et al, 2013). However, the exact mechanism underlying proteinmalnourishment leukopenia remains unknown.…”

Prévalence et déterminants de l’anémie chez le jeune enfant en Afrique francophone – Implication de la carence en fer

“…En effet, le renouvellement cellulaire rapide du tissu hémato-poïétique exige un apport important de nutriments, en particulier de protéines, mais aussi de vitamines B9 (folates) et B12, et bien sûr de fer. Des travaux expérimentaux sur des rongeurs en situation de carence protéique ont montré une réduction de la prolifération des cellules progénitrices pluripotentes, à l'origine des hématies [37,38] …”

Influência da L-glutamina sobre aspectos imunomodulatórios de células tronco mesenquimais medulares em situação de desnutrição proteico-energética

“…Além disso, a DPE pode alterar o processo de diferenciação de CTMs e, consequentemente, alterar a formação dos microabientes indutíveis da hematopoese, de forma a prejudicar a formação do compartimento estromal medular e alterar o perfil de produção de citocinas, influenciando assim a hematopoese (CUNHA et al, 2013 Neste trabalho, optamos por trabalhar com CTMs em baixa passagem (P1), pois a manipulação in vitro dessas células resulta na perda da sua capacidade de proliferação e diferenciação, respectivamente, a partir da 3 a e 6 a passagens (BONAB et al, 2006;AYATOLLAHI et al, 2012).…”

“…Recentemente, nosso grupo relatou que as CTMs provenientes de animais desnutridos tendem a se diferenciar em adipócitos, comprometendo a manutenção de um estroma de suporte adequado para o processo de hemopoese (CUNHA et al, 2013). Até o momento, não existem estudos que abordam a influência da desnutrição sobre aspectos proliferativos e imunomodulatórios das CTMs.…”