2. Academic Validation
  3. Modulation of NLRP3 inflammasomes activation contributes to improved survival and function of mesenchymal stromal cell spheroids

Modulation of NLRP3 inflammasomes activation contributes to improved survival and function of mesenchymal stromal cell spheroids

  • Mol Ther. 2022 Dec 24;S1525-0016(22)00718-3. doi: 10.1016/j.ymthe.2022.12.014.
Duc-Vinh Pham 1,  Prakash Shrestha 2,  Thi-Kem Nguyen 3,  Junhyeung Park 2,  Mahesh Pandit 3,  Jae-Hoon Chang 3,  Soo Young Kim 3,  Dong-Young Choi 3,  Sung Soo Han 4,  Inho Choi 5,  Gyu Hwan Park 6,  Jee-Heon Jeong 7,  Pil-Hoon Park 8
Affiliations

Affiliations

  • 1 College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea, 38541; Department of Pharmacology, Hanoi University of Pharmacy, Hanoi, Viet Nam.
  • 2 Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Republic of Korea, 16419.
  • 3 College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea, 38541.
  • 4 Research Institute of cell culture, Yeungnam University, Gyeongsan, Republic of Korea, 38541; School of Chemical Engineering, Yeungnam University, Gyeongsan, Republic of Korea, 38541.
  • 5 Research Institute of cell culture, Yeungnam University, Gyeongsan, Republic of Korea, 38541; Department of Medical Biotechnology, Yeungnam University, Gyeongsan, Republic of Korea, 38541.
  • 6 College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea, 41566.
  • 7 Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Republic of Korea, 16419. Electronic address: jeeheon@skku.edu.
  • 8 College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea, 38541; Research Institute of cell culture, Yeungnam University, Gyeongsan, Republic of Korea, 38541. Electronic address: parkp@yu.ac.kr.
PMID: 36566348 DOI: 10.1016/j.ymthe.2022.12.014
Abstract

Mesenchymal stem cells (MSCs) are ubiquitous multipotent cells that exhibit significant therapeutic potentials in a variety of disorders. Nevertheless, their clinical efficacy is limited owing to poor survival, low rate of engraftment, and impaired potency upon transplantation. Spheroidal three-dimensional (3D) culture of MSCs (MSC3D) has been proved to better preserve their in vivo functional properties. However, the molecular mechanisms underlying the improvement in MSC function by spheroid formation are not clearly understood. NLRP3 inflammasomes, a key component of the innate immune system, have recently been shown to play a role in cell fate decision of MSCs. The present study examined the role of NLRP3 inflammasomes in the survival and potency of MSC spheroids. We found that MSC3D led to decreased activation of NLRP3 inflammasomes through alleviation of ER stress in an autophagy-dependent manner. Importantly, downregulation of NLRP3 inflammasomes signaling critically contributes to the enhanced survival rate in MSC3D through modulation of Pyroptosis and Apoptosis. The critical role of NLRP3 inflammasomes suppression in the enhanced therapeutic efficacy of MSC spheroids was further confirmed in an in vivo mouse model of DSS-induced colitis. These findings suggest that 3D culture confers survival and functional advantages to MSCs by suppressing NLRP3 inflammasomes activation.

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