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

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 proven 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 inflammasome 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 inflammasome activation.

• Authors: Duc-Vinh Pham, Prakash Shrestha, Thi-Kem Nguyen, Junhyeung Park, Mahesh Pandit, Jae-Hoon Chang, Soo Young Kim, Dong-Young Choi, Sung Soo Han, Inho Choi, Gyu Hwan Park, Jee-Heon Jeong, Pil-Hoon Park
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 31 Issue 3 Pg. 890-908 (03 01 2023) ISSN: 1525-0024 [Electronic] United States
• PMID: 36566348 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse

Topics

• Animals
• Mice
• Colitis (chemically induced, genetics, immunology)
• Inflammasomes (genetics, immunology)
• Mesenchymal Stem Cells (immunology)
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics)
• Signal Transduction
• Cell Culture Techniques, Three Dimensional