Mesenchymal stem cells in alleviating sepsis-induced mice cardiac dysfunction via inhibition of mTORC1-p70S6K signal pathway

Abstract

Sepsis-induced cardiac dysfunction remains a major cause of morbidity and mortality in patients suffered from severe trauma. Mesenchymal stem cells (MSCs) -based treatment has been verified as a promising approach to mitigate the sepsis-induced cardiac dysfunction, but the mechanism is still ambiguous. Thus, our study was designed to explore the potential role of MSCs in sepsis-induced cardiac dysfunction. In vivo bioluminescence imaging revealed 80% acute donor cell death of bone marrow-derived MSCs (BM-MSCs) within 3 days after transplantation. However, echocardiography demonstrated that systolic function in wild-type mice group were reduced after sepsis, while the cardiac function was relatively well persevered in cardiac-conditional deletion of Raptor (component of mTORC1 complex) mice group. Raptor KO group treated with BM-MSCs appeared better cardiac function than other groups (P<0.05). In vitro cell study revealed that co-culture of H9C2 (Raptor-Knock down) and BM-MSC could attenuate the level of proinflammatory cytokines and promote the expression of anti-inflammatory cytokine accompanied by mTORC2-Akt activation (P<0.05). In contrast, co-culture H9C2 (Raptor-O.E) and BM-MSC could aggravate the inflammatory response accompanied by the activation of mTORC1-p70S6K and inhibition of mTORC2-Akt (P<0.05). The immunomodulatory property of MSC is related to the inhibition of mTORC1-p70S6K and activation of mTORC2-Akt signaling pathway. mTORC1-p70S6K and mTORC2-Akt pathways were involved in the therapeutic adjuncts of MSC. The possible mechanism due to MSC`s immunomodulatory property through activation of mTORC2-Akt and inhibition of mTORC1-p70S6K signal pathways which may lead to modulate the expression of inflammation cytokines.

The ATP-Binding Cassette Gene ABCF1 Functions as an E2 Ubiquitin-Conjugating Enzyme Controlling Macrophage Polarization to Dampen Lethal Septic Shock

“…Previous studies have also shown modulation of SIRS phase of sepsis and sepsis-induced mortality by bone marrow transplant (Lorigados et al, 2018, Huang et al, 2017. We hypothesized that ABCF1 deficiency in bone-marrow-derived haemopoietic cells was responsible for this increase in susceptibility to developing sepsis.…”

Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin‐conferred cardioprotection against myocardial ischemia/reperfusion injury

“…Minicircle vectors were used to transfect CMs in accordance with the manufacturer's instructions (System Biosciences, CA, USA). Adenovirus vectors for MT2 silencing and MT2 overexpression as well as control lacZ vector were commercially purchased from GeneChem Co., Ltd (Shanghai, China) and transfected as we previously described . To inhibit Notch1 expression, cells were transfected with small interfering RNA against Notch1 conjugated with Lipofectamine 3000 for 6 hours.…”

“…Adenovirus vectors for MT2 silencing and MT2 overexpression as well as control lacZ vector were commercially purchased from GeneChem Co., Ltd (Shanghai, China) and transfected as we previously described. 36 To inhibit Notch1 expression, cells were transfected with small interfering RNA against Notch1 conjugated with Lipofectamine 3000 for 6 hours. All the siRNA agents were purchased from Santa Cruz (Santa Cruz, Dallas, TX, USA).…”

Mesenchymal stromal cell–based therapies for acute kidney injury: progress in the last decade

“…route. 15,20,27,28 Interestingly, in animal models of hematological conditions, the effectiveness of MSC therapy was comparable or superior after i.p. compared with i.v.…”

“…), subcutaneous, and intramuscular injections. [15][16][17][18][19][20][21] In one such study, i.v.-administered adipose-derived MSCs (both live and heat-inactivated) were found not to migrate to an inflammatory site, with most remaining localized to the lungs. 21 Similar findings were made using postmortem quantification of an MSC-delivered radioactive isotope to investigate the distribution of i.v.-administered MSCs to individual tissue including the kidneys.…”