Engineered MSC Aggregates with E/N-Cadherin and IL-6 Preconditioning for the Treatment of Systemic Sclerosis

Yue Zhang; Mengyuan Qian; Yirui Shi; Jiaxu Cao; Min Xu; Xin Wen; Yunxia Yan; Sha Liu; Hongwei Chen; Shanshan Liu; Jun Yang; Lingyun Sun

doi:10.1002/adhm.202500663

Engineered MSC Aggregates with E/N-Cadherin and IL-6 Preconditioning for the Treatment of Systemic Sclerosis

Adv Healthc Mater. 2025 Jun 11:e2500663. doi: 10.1002/adhm.202500663. Online ahead of print.

Authors

Yue Zhang¹, Mengyuan Qian², Yirui Shi³, Jiaxu Cao², Min Xu⁴, Xin Wen⁵, Yunxia Yan⁵, Sha Liu⁴, Hongwei Chen⁴, Shanshan Liu⁵, Jun Yang², Lingyun Sun^{3

6}

Affiliations

¹ Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, 321 Zhongshan Road, Nanjing, 210008, P. R. China.
² The Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Science, Nankai University, 94 Weijin Road, Tianjin, 300071, P. R. China.
³ Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, 321 Zhongshan Road, Nanjing, 210008, P. R. China.
⁴ Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing, 210008, P. R. China.
⁵ Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, P. R. China.
⁶ Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, P. R. China.

PMID: 40500954
DOI: 10.1002/adhm.202500663

Abstract

Umbilical cord-derived mesenchymal stromal cells (MSCs) transplantation is a promising therapy for systemic sclerosis (SSc) because of their distinctive antifibrotic and immunomodulatory properties. To enhance the effects of MSCs transplantation, novel engineered MSC aggregates preconditioned with human E/N-cadherin fusion protein (hE/N-cad-Fc) and interleukin-6 (IL-6) for SSc treatment are fabricated and named 3D-Cad/IL6-MSCs. These novel-engineered MSC aggregates possess tighter cellular cohesion and exhibit enhanced antiapoptotic, immunosuppressive, and proangiogenic capabilities according to transcriptomic analyses. Moreover, 3D-Cad/IL6-MSCs have improved immunoregulatory effects on peripheral blood mononuclear cells (PBMCs), CD4⁺ T cells, and CD8⁺ T cells in vitro because of the synergistic preconditioning from IL-6 and bioactive hE/N-cad-Fc. Upon intravenous injection, 3D-Cad/IL6-MSCs significantly mitigate skin and lung fibrosis and prolong the retention duration in bleomycin (BLM)-induced SSc mouse model. In detail, they suppress excessive infiltration of macrophages and T cells in the injured skin and lungs and reestablish the immune equilibrium of circulating CD4⁺ T-cell subsets in vivo. These results suggest that 3D-Cad/IL6-MSCs are ideal candidates for SSc therapy and optimize the clinical utilization of MSCs.

Keywords: IL‐6; aggregates; cadherin; mesenchymal stromal cells; systemic sclerosis.

Abstract

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