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.
Yue Zhang  1 ,  Mengyuan Qian  2 ,  Yirui Shi  3 ,  Jiaxu Cao  2 ,  Min Xu  4 ,  Xin Wen  5 ,  Yunxia Yan  5 ,  Sha Liu  4 ,  Hongwei Chen  4 ,  Shanshan Liu  5 ,  Jun Yang  2 ,  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.
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