Research Highlights

Engineering of hybrid spheroids of mesenchymal stem cells and drug depots for immunomodulating effect in islet xenotransplantation

Tiep Tien Nguyen, Duc-Vinh Pham, Junhyeung Park, Cao Dai Phung, Mahesh Raj Nepal, Mahesh Pandit, Manju Shrestha, Youlim Son, Mili Joshi, Tae Cheon Jeong, Pil-Hoon Park, Dong-Young Choi, Jae-Hoon Chang, Ju-Hyun Kim, Jae-Ryong Kim, Il-Kug Kim, Chul Soon Yong, Jong Oh Kim, Jong-Hyuk Sung, Hu-Lin Jiang, Hyung-Sik Kim, Simmyung Yook, Jee-Heon Jeong

Immunomodulation is an essential consideration for cell replacement procedures. Unfortunately, lifelong exposure to non-specific systemic immunosuppression results in immunodeficiency and has toxic effects on non-immune cells.
In this study, we report an effective methodology to potentiate the immunomodulatory properties of MSCs via engineering hybrid spheroids with rapamycin (RAP)-releasing poly(lactic-co-glycolic acid) (PLGA) microparticle depots (RAP-MPs). The devised hybrid spheroids were locoregionally transplanted with rat pancreatic islets into diabetic C57BL/6 mice to prevent the strong immune rejection of these xeno-sourced islets. This approach only required a single treatment with a low-dose immunosuppressant but resulted in long-term effects on immunosuppression.
Hybrid spheroids were rapidly formed by incubating cell-particle mixture in methylcellulose solution while maintaining high cell viability. RAP-MPs were uniformly distributed in hybrid spheroids and sustainably released RAP for ~3 weeks. Locoregional transplantation of hybrid spheroids containing low-doses of RAP-MPs (200-4000 ng RAP/recipient) significantly prolonged islet survival times and promoted the generation of regional regulatory T cells. Enhanced Programmed Death-Ligand 1 (PD-L1) expression by MSCs was found to be responsible for the immunomodulatory performance of hybrid spheroids. Our results suggest that these hybrid spheroids offer a promising platform for the efficient use of MSCs in the transplantation field. This study was published in Science Advances in August 2022 (Nguyen et al., Sci. Adv. 8, eabn8614 (2022)).