In a recent issue of Hepatology, Herrera et al. reported that human bone-marrow derived mesenchymal stem cells (hMSCs) provided protection from death from fulminant liver failure (FLF) induced by intraperitoneal injection of D-galactosamine/lipopolysaccharide (GalN/LPS) in severe combined immune deficiency (SCID) mice. SCID mice lack functional T and B cells and have been used extensively in xenotransplantation. However, the mice still possess normal natural killer (NK) cells. Successful xenotransplantation in SCID mice is dependent on reduction of NK cells activity by conventional total body irradiation or treatment with anti-NK cell antibodies. No information was provided in this study on suppression of NK cell activity suppression prior to hMSCs injection. Activated NK cells can lyse hMSCs.[4, 5] The possible mechanisms are as follows (Fig. 1).
In normal cells, the expression of human leukocyte antigen (HLA) class I molecules (a classic MHC class 1 molecule) could interact with these inhibitory receptors (KIR) on NK cells and prevent NK cells from being activated. However, hMSCs have low-level expression of HLA class I molecules, and this would lessen inhibitory interactions, leading to NK-cell activation and then hMSC lysis.
The hMSCs express the activating NK cell-receptor (KAR) ligands (PVR, Nectin-2, and ULBP3), which can be recognized by DNAM-1 and NKG2D of NK cells, contributing to NK cell-mediated lysis.
Hence, suppression of the activation of NK cells in SCID mice is necessary before hMSCs injection.
Jin-Zhong Dong, M.D.
Li-Ping Wang, M.D.
Chun-Wei Shi, M.D.
Sai-Nan Zhang, M.D.
Ming-Qin Lu, M.D.
Department of Infection and Liver Diseases, Liver Research Center, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, P.R. China