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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Individual response to mTOR inhibition in delaying replicative senescence of mesenchymal stromal cells

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Autor(es):
Antonioli, Eliane [1] ; Torres, Natalia [1] ; Ferretti, Mario [1] ; Piccinato, Carla de Azevedo [1] ; Sertie, Andrea Laurato [1]
Número total de Autores: 5
Afiliação do(s) autor(es):
[1] Hosp Israelita Albert Einstein, Sao Paulo, SP - Brazil
Número total de Afiliações: 1
Tipo de documento: Artigo Científico
Fonte: PLoS One; v. 14, n. 1 JAN 31 2019.
Citações Web of Science: 2
Resumo

Background aims Delaying replicative senescence and extending lifespan of human mesenchymal stromal cells (MSCs) may enhance their potential for tissue engineering and cell based therapies. Accumulating evidence suggests that inhibitors of the mTOR signaling pathway, such as rapamycin, constitute promising pharmacological agents to retard senescence and extend stemness properties of various progenitor cell types. Here, we investigated whether the ability of rapamycin to postpone replicative senescence varies among bone marrow MSC samples (BM-MSCs) derived from different healthy donors, and explored the molecular mechanisms that drive rapamycin-mediated lifespan increment. Methods BM-MSCs at early passages were serially passaged either in absence or continuous presence of rapamycin and the number of cell population doublings until growth arrest was measured. The inhibition of mTOR signaling was assessed by the phosphorylation status of the downstream target RPS6. The expression levels of several senescence and pluripotency markers at early and late/senescent passages were analyzed by RT-qPCR, flow cytometry and western blot. Results We found that the lifespan extension in response to the continuous rapamycin treatment was highly variable among samples, but effective in most BM-MSCs. Despite all rapamycin-treated cells secreted significantly reduced levels of IL6, a major SASP cytokine, and expressed significantly higher levels of the pluripotency marker NANOG, the expression patterns of these markers were not correlated with the rapamycin-mediated increase in lifespan. Interestingly, rapamycin-mediated life-span extension was significantly associated only with repression of p16(INK4A) protein accumulation. Conclusions Taken together, our results suggest that some, but not all, BM-MSC samples would benefit from using rapamycin to postpone replicative arrest and reinforce a critical role of p16(INK4A) protein downregulation in this process. (AU)

Processo FAPESP: 14/25646-3 - Investigação dos efeitos moleculares e celulares de mutações no gene Reln identificadas em pacientes com Transtornos do Espectro Autista
Beneficiário:Andréa Laurato Sertié
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 12/00831-7 - Condrócitos osteoartríticos e células mesenquimais: relação entre moléculas inflamatórias e da matriz extracelular
Beneficiário:Mario Ferretti Filho
Linha de fomento: Auxílio à Pesquisa - Regular