Heterospheroid formation improves therapeutic efficacy of mesenchymal stem cells in murine colitis through immunomodulation and epithelial regeneration.
basic_science · Level V
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- Record sourced from PubMed, PMID 33730631.
- Also identified by DOI 10.1016/j.biomaterials.2021.120752.
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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 (MSC<sub>HS</sub>), to achieve local drug delivery to the cells. Notably, MSC<sub>HS</sub> exhibited resistance for senescence-associated phenotype and oxidative stress-induced apoptosis compared to 3D-cultured MSCs (MSC<sub>3D</sub>), as well as to 2D-cultured cells (MSC<sub>2D</sub>) in vitro. In a murine model of colitis, MSC<sub>3D</sub> and MSC<sub>HS</sub> exhibited enhanced anti-inflammatory impact than MSC<sub>2D</sub>via attenuating neutrophil infiltration and regulating helper T cell (Th) polarization into Th1 and Th17 cells. Interestingly, MSC<sub>HS</sub> provided better therapeutic outcomes compared to MSC<sub>3D</sub>, partially due to their enhanced survival capacity in vivo. Moreover, we found that MSC-derived paracrine factor, prostaglandin E<sub>2</sub> (PGE<sub>2</sub>), can directly drive the epithelial regeneration process by inducing specialized tissue-repairing cell generation using the intestinal organoid culture. Importantly, MSC<sub>3D</sub> and MSC<sub>HS</sub> displayed an outstanding regeneration-inducing potency compared to MSC<sub>2D</sub> owing to their superior PGE<sub>2</sub> secretion. Taken together, we suggest a convergent strategy of MSC<sub>HS</sub> 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.
Medical subject headings
- Colitis
- Mesenchymal Stem Cell Transplantation
- Mesenchymal Stem Cells