Heterospheroid formation improves therapeutic efficacy of mesenchymal stem cells in murine colitis through immunomodulation and epithelial regeneration

Shobha Regmi, Yoojin Seo, Ji Su Ahn, Shiva Pathak, Suman Acharya, Tiep Tien Nguyen, Simmyung Yook, Jong Hyuk Sung, Jun Beom Park, Jong Oh Kim, Chul Soon Young, Hyung Sik Kim, Jee Heon Jeong

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


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.

Original languageEnglish
Article number120752
Publication statusPublished - 2021 Apr

Bibliographical note

Funding Information:
This study was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (grant numbers; NRF-2015R1A5A2009124 , 2018R1A5A2023879 , 2019R1A2C2085876 and 2020R1C1C1004733 ) and was carried out with the support of " Cooperative Research Program for Agriculture Science and Technology Development (Project No. PJ015596 )" Rural Development Administration, Republic of Korea.

Publisher Copyright:
© 2021 Elsevier Ltd

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Bioengineering
  • Ceramics and Composites
  • Biomaterials
  • Mechanics of Materials


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