Effects of combustible cigarettes and heated tobacco products on immunomodulatory and hepatoprotective properties of mesenchymal stem cells in acute liver failure.

Numerous experimental and clinical studies have indicated that mesenchymal stem cells (MSCs) and their secretome can modulate progression of acute liver failure (ALF). Our earlier research has demonstrated that exposure to cigarette smoke significantly diminished these capabilities, rendering MSCs incapable of mitigating hepatic inflammation induced by immune cells. It remains uncertain whether heated tobacco products (HTPs), which produce fewer hazardous chemicals than combustible cigarettes, would similarly impact MSC function. In this study, we cultured murine Bone Marrow-Derived Mesenchymal Stem Cells (BM-MSCs) in Aqe (aqueous extracts) generated from combustible cigarettes (CC) or HTPs assessed their therapeutic efficiency in α-GalCer (alpha-galactosylceramide)-induced fulminant hepatitis in C57BL/6 mice. We also co-cultured human PDL-MSCs (Periodontal Ligament-derived Mesenchymal Stem Cells) with activated CD4⁺ T lymphocytes and NKT cells in a transwell system to validate these findings in a human setting. Consistent with our earlier work, cigarette smoke-exposed MSCs failed to attenuate hepatocyte damage and did not suppress the expansion of inflammatory and hepatotoxic immune cells in injured livers. By contrast, HTPs-exposed MSCs retained a certain amount of their immunosuppressive and hepatoprotective capacity- serum transaminase levels were lower, liver necrosis was less extensive, and fewer pro-inflammatory NK, NKT, Th1, Th17, and CD8⁺ T cells infiltrated the liver parenchyma. The human in vitro experiments yielded comparable results, indicating that HTPs impair MSCs' function to a lesser extent than cigarette smoke.