Wharton's jelly-derived mesenchymal stem cells attenuate sepsis-induced organ injury partially via cholinergic anti-inflammatory pathway activation

Autor(es):Mostrar menos -

Condor Capcha, Jose Manuel ^{[1, 2]} ; Rodrigues, Camila Eleuterio ^[1] ; Moreira, Roberto de Souza ^{[1, 3]} ; Silveira, Marcelo Duarte ^[1] ; Dourado, Paulo ^[4] ; dos Santos, Fernando ^[4] ; Irigoyen, Maria Claudia ^[4] ; Jensen, Leonardo ^[4] ; Garnica, Margoth Ramos ^[2] ; Noronha, Irene L. ^[2] ; Andrade, Lucia ^[1] ; Gomes, Samirah Abreu ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Lab Basic Res, Sch Med, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Lab Genet Cellular Biol & Mol Biol, Sch Med, Sao Paulo - Brazil

^[3] Fed Univ Goias Catalao, Catalao - Brazil

^[4] Univ Sao Paulo, Heart Inst, Sch Med, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY; v. 318, n. 1, p. R135-R147, JAN 2020.
• Citações Web of Science: 0

Resumo

Sepsis induces organ dysfunction due to overexpression of the inflammatory host response, resulting in cardiopulmonary and autonomic dysfunction, thus increasing the associated morbidity and mortality. Wharton's jellyderived mesenchymal stem cells (WJ-MSCs) express genes and secrete factors with anti-inflammatory properties, neurological and immunological protection, as well as improve survival in experimental sepsis. The cholinergic anti-inflammatory pathway (CAP) is mediated by alpha 7-nicotinic acetylcholine receptors (alpha 7nAChRs). which play an important role in the control of systemic inflammation. We hypothesized that WJ-MSCs attenuate sepsis-induced organ injury in the presence of an activated CAP pathway. To confirm our hypothesis, we evaluated the effects of WJ-MSCs as a treatment for cardiopulmonary injury and on neuroimmunomodulation. Male Wistar rats were randomly divided into four groups: control (sham-operated); cecal ligation and puncture (CLP) alone; CL.P+WJ-MSCs (1 x 10(6) cells, at 6 h post-CLP); and CLP+methyllycaconifine (MLA)+WJ-MSCs (5 mg/kg body wt, at 53 h post-CLP, and 1 x 10(6) cells, at 6 h post-CLP. respectively). All experiments, including the assessment of echocardiographic parameters and heart rate variability, were performed 24 h after CLP. WJ-MSC treatment attenuated diastolic dysfunction and restored baroreflex sensitivity. WJ-MSCs also increased cardiac sympathetic and cardiovagal activity. WJ-MSCs reduced leukocyte infiltration and proinflammatory cytokines, effects that were abolished by administration of a selective alpha 7nAChR antagonist (MLA). In addition, WJ-MSC treatment also diminished apoptosis in the lungs and spleen. In cardiac and splenic tissue, WJ-MSCs downregulated alpha 7nAChR expression, as well as reduced the phospho-STAT3-tototal STAT3 ratio in the spleen. WJ-MSCs appear to protect against sepsis-induced organ injury by reducing systemic inflammation, at least in part, via a mechanism that is dependent on an activated CAP. (AU)

• Processo FAPESP: 10/19012-0 - Avaliação da terapia com células-tronco hematopoiéticas na doença renal crônica em cães
• Beneficiário: Lucia da Conceição Andrade
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 15/21308-9 - Células-tronco mesenquimais derivados da geleia de Wharton na injuria cardiopulmonar e neuroimunomodulação sistêmica na sepse
• Beneficiário: José Manuel Cóndor Capcha
• Modalidade de apoio: Bolsas no Brasil - Doutorado