Umbilical cord mesenchymal stem cells with reduced immune rejection and enhanced efficacy for intervention in severe acute pancreatitis

This study is led by Dr. Yu Zheng (Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University), MD. Kun Jiang (Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University), and Dr. Qian Yao (Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University).

MSCs exhibit considerable plasticity in modulating inflammation. In the absence of a stimulus, they do not demonstrate immune regulatory effects. However, immune regulatory molecules are considerably increased in response to inflammatory mediators, thereby exhibiting anti-inflammatory actions. To date, only type II interferon (IFNγ) has been recognized as a promising pharmacological agent for the pretreatment of MSCs in clinical investigations for disease management. This effect is attributed to the substantial augmentation in the expression of PD-L1, iNOS, and IDO subsequent to IFNγ pretreatment, which are the principal immunoregulatory molecules synthesized by MSCs.

To identify effective and low-toxicity medicines for the pretreatment of MSCs in conjuction with IFNγ, natural active monomers from traditional Chinese medicine were evaluated. Chaiqin Chengqi Decoction (CQCQD), a clinically proven TCM recipe for the treatment of SAP, with rhubarb serving as the principal drug, was selected for further investigation into its active monomers. The preliminary experiment indicated that both emodin and aloe emodin (AE) functioned in a synergistic manner with IFNγ in upregulating the immunosuppressive molecules of MSCs.

The combination of IFNγ and rhubarb active components, particularly AE, enhanced the expression of IDO and PD-L1 at both the RNA and protein levels in umbilical cord mesenchymal stem cells (UMSCs). This observation evidenced by western blot and flow cytometry.

Excessively high drug concentrations resulted in the inhibition of MSC proliferation. AE-loaded nanoparticles were thus prepared and effectively controlled the inhibition effect within a manageable range by means of sustained release of AE. Furthermore, these nanoparticles were demonstrated to have a boosting effect in comparison to the free drug, indicating that nano-encapsulation preserves the drug's efficacy.

However, in the preliminary experiment, the combination of AE with IFN-γ for the pretreatment of UMSCs (I-AE UMSCs) proved less successful than the IFN-γ pretreated UMSCs group (I-UMSCs) in mitigating inflammation. This outcome was likely attributable to augmented production of HLA-I and HLA-II class molecules in UMSCs following the I-AE treatment, with HLA-II predominantly facilitating immunological rejection in CD4+T cells. The transient transfection of siRNA effectively silenced the class II transactivator (CIITA) gene expression of UMSCs, thereby interfering with HLA-II expression to avert immune rejection.

UMSCs pretreated by I-AE with CIITA silencing inhibited CD4+T cells activation in an in vitro co-culture assay. Additionally, in mouse in vivo experiments, they preserved pancreatic structure as evidenced by diminished acinar cell death, reduced pancreatic edema and inflammation, and significantly lowered serum amylase levels. The encouraging potential of UMSCs with CIITA gene silencing combined with I-AE pretreatment holds promise for clinical application in treatment of severe acute pancreatitis.

See the article: 

The potency of aloe emodin-loaded nanoparticles in conjunction with IFN-γ for the pretreatment of mesenchymal stem cells with class II transactivator silence to alleviate severe acute pancreatitis

https://onlinelibrary.wiley.com/doi/10.1002/mba2.70001