Heterospheroid formation improves therapeutic efficacy of mesenchymal stem cells in murine colitis through immunomodulation and epithelial regeneration. (April 2021)

• Record Type: Journal Article
• Authors: Regmi, Shobha; Seo, Yoojin; Ahn, Ji-Su; Pathak, Shiva; Acharya, Suman; Nguyen, Tiep Tien; Yook, Simmyung; Sung, Jong-Hyuk; Park, Jun-Beom; Kim, Jong Oh; Young, Chul Soon; Kim, Hyung-Sik; Jeong, Jee-Heon
• Is Part Of: Biomaterials. Volume 271(2021)
• Publication Date: 2021-04
• Subjects: Heterospheroid -- Quercetin -- Inflammatory bowel disease -- Intestinal organoids -- Epithelial regeneration -- Immunomodulation; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2021.120752
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: Tissue repairing capacity and immunomodulatory effects of mesenchymal stem cells (MSCs) have been extensively utilized for treating various inflammatory disorders; however, inconsistent efficacy and therapeutic outcomes due to low survival rate after transplantation often restrain their clinical potential. To overcome these limitations, 3-dimensional culture (3D-culture) was established to augment stemness and paracrine functions of MSCs, although hypoxic stress at the core often leads to unexpected cell death. Thus, we designed a novel strategy to improve the microenvironment of MSCs by creating heterospheroids (HS) consisting of MSCs and quercetin (QUR)-loaded microspheres (MSCHS ), to achieve local drug delivery to the cells. Notably, MSCHS exhibited resistance for senescence-associated phenotype and oxidative stress-induced apoptosis compared to 3D-cultured MSCs (MSC3D ), as well as to 2D-cultured cells (MSC2D ) in vitro . In a murine model of colitis, MSC3D and MSCHS exhibited enhanced anti-inflammatory impact than MSC2D via attenuating neutrophil infiltration and regulating helper T cell (Th) polarization into Th1 and Th17 cells. Interestingly, MSCHS provided better therapeutic outcomes compared to MSC3D, partially due to their enhanced survival capacity in vivo . Moreover, we found that MSC-derived paracrine factor, prostaglandin E2 (PGE2 ), can directly drive the epithelial regeneration process by inducing specialized tissue-repairing cell generation using the intestinal organoid culture. Importantly, MSC3D and MSCHS displayed an outstanding regeneration-inducing potency compared to MSC2D owing to their superior PGE2 secretion. Taken together, we suggest a convergent strategy of MSCHS formation with reactive oxygen species (ROS) scavenger, QUR, which can maximize the inflammation-attenuating and tissue-repairing capacity of MSCs, as well as the engraftment efficiency after transplantation.