E2 pretreatment alleviates aggregation of intravenously injected mesenchymal stem cells in TBI by regulating BRG1 to affect adhesion.

BACKGROUND: Human umbilical cord mesenchymal stem cells (hUMSCs) are considered an effective prospect for treating TBI, but they tend to accumulate in the lungs after intravenous injection, hindering further clinical translation. Brahma-related gene 1(BRG1) can be influenced by estrogen to regulate adhesion, and ourprevious studies have found that the expression of BRG1 in lungs increases after TBI. However, the relationship between BRG1, estrogen, TBI, and stem cell lung aggregation is not clear. METHODS: By regulating the expression levels of BRG1 in vascular endothelial cells and hUMSCs, Western Blot and immunohistochemistry were used to explore its changes in adhesion and possible mechanisms; used in vivo bioluminescenece imaging analysis, real-time tracking the distribution of stem cells after transplantation; and therapeutic drug E2 is introduced to observe the effect of changes in BRG1 expression on the aggregation of hUMSCs in the lungs of model animals, as well as the therapeutic effect of E2-pretreated hUMSCs on inflammation after TBI. RESULTS: After TBI, the retention of hUMSCs in the lungs was higher in the TBI groups than in the Sham groups, and the level of BRG1 in lung was higher in the TBI groups than in the Sham groups; the expression of BRG1 in HUVECs, HPAECs, and hUMSCs treated with TNF-α and LPS were higher than those in the control groups, showing dose- and time-dependent effects. E2 can inhibit the expression of BRG1 and adhesion proteins; after intervention with estrogen receptor inhibitor (ICI 182780) and NF-κ B inhibitor SC75741, BRG1 expression increased and adhesion protein decreased; E2-pretreated MSCs can reduce pulmonary retention, and has no adverse effects on the inflammatory response for TBI. CONCLUSIONS: Our study proposes the inflammatory state after TBI leads to enhanced adhesion of blood vessels and transplanted stem cells, which is a contributing factor to the increased aggregation of intravenous hUMSCs in the lungs, E2 can alleviate pulmonary aggregation in stem cell intravenous injection therapy.