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- Title
Intraperitoneally Delivered Umbilical Cord Lining Mesenchymal Stromal Cells Improve Survival and Kidney Function in Murine Lupus via Myeloid Pathway Targeting.
- Authors
Chua, Alvin Wen Choong; Guo, Dianyang; Tan, Jia Chi; Lim, Frances Ting Wei; Ong, Chee Tian; Masilamani, Jeyakumar; Lim, Tony Kiat Hon; Hwang, William Ying Khee; Lim, Ivor Jiun; Chen, Jinmiao; Phan, Toan Thang; Fan, Xiubo
- Abstract
To determine the therapeutic efficacy of human umbilical cord lining mesenchymal stromal cells (CL-MSCs) (US Patent number 9,737,568) in lupus-prone MRL/lpr (Faslpr) mice and elucidate its working mechanisms. A total of 4 doses of (20–25) × 106 cells/kg of CL-MSCs was given to 16-week-old female Faslpr mice by intraperitoneal injection. Three subsequent doses were given on 17 weeks, 18 weeks, and 22 weeks, respectively. Six-week-old Faslpr mice were used as disease pre-onset controls. Mice were monitored for 10 weeks. Mouse kidney function was evaluated by examining complement component 3 (C3) deposition, urinary albumin-to-creatinine ratio (ACR), and lupus nephritis (LN) activity and chronicity. Working mechanisms were elucidated by flow cytometry, Luminex/ELISA (detection of anti-dsDNA and isotype antibodies), and RNA sequencing. CL-MSCs improved mice survival and kidney function by reducing LN activity and chronicity and lymphocyte infiltration over 10 weeks. CL-MSCs also reduced urinary ACR, renal complement C3 deposition, anti-dsDNA, and isotype antibodies that include IgA, IgG1, IgG2a, IgG2b, and IgM. Immune and cytokine profiling demonstrated that CL-MSCs dampened inflammation by suppressing splenic neutrophils and monocytes/macrophages, reducing plasma IL-6, IL-12, and CXCL1 and stabilizing plasma interferon-γ and TNF-α. RNA sequencing further showed that CL-MSCs mediated immunomodulation via concerted action of pro-proinflammatory cytokine-induced chemokines and production of nitric oxide in macrophages. CL-MSCs may provide a novel myeloid (neutrophils and monocytes/macrophages)-targeting therapy for SLE.
- Subjects
KIDNEY physiology; STROMAL cells; COMPLEMENT (Immunology); CELL survival; NEUTROPHILS; MESENCHYMAL stem cells; MYELOID cells; UMBILICAL cord
- Publication
International Journal of Molecular Sciences, 2023, Vol 24, Issue 1, p365
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms24010365