Human embryonic stem cell-derived mesenchymal cells preserve kidney function and extend lifespan in NZB/W F1 mouse model of lupus nephritis

• Published in: Scientific reports Vol. 5; no. 1; p. 17685
• Main Authors: Thiel, Austin, Yavanian, Gregory, Nastke, Maria-Dorothea, Morales, Peter, Kouris, Nicholas A., Kimbrel, Erin A., Lanza, Robert
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.12.2015; Nature Publishing Group
• Subjects: 631/1647/334/1874/345; 631/532/1360; 631/532/2074; 631/532/2117; Adult Stem Cells - metabolism; Animals; Autoimmune diseases; CD3 antigen; Cell culture; Clinical trials; Creatinine; Disease Models, Animal; Heterografts; Human Embryonic Stem Cells - metabolism; Humanities and Social Sciences; Humans; Immunoregulation; Inflammation; Interleukin 6; Kidney - metabolism; Kidney - pathology; Kidney - physiopathology; Kidneys; Life span; Lipopolysaccharides; Lupus; Lupus nephritis; Lupus Nephritis - metabolism; Lupus Nephritis - pathology; Lupus Nephritis - physiopathology; Lupus Nephritis - therapy; Lymphocytes; Lymphocytes T; Mesenchymal Stem Cell Transplantation; Mesenchymal Stromal Cells - metabolism; Mesenchyme; Metastases; Mice; multidisciplinary; Nephritis; Proteinuria; Science; Serum levels; Statistical analysis; Stem cells; Stromal cells; Systemic lupus erythematosus; Tumor necrosis factor-α
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep17685

Adult tissue-derived mesenchymal stromal cells (MSCs) are showing promise in clinical trials for systemic lupus erythematosus (SLE). However, the inability to manufacture large quantities of functional cells from a single donor as well as donor-dependent variability in quality limits their clinical utility. Human embryonic stem cell (hESC)-derived MSCs are an alternative to adult MSCs that can circumvent issues regarding scalability and consistent quality due to their derivation from a renewable starting material. Here, we show that hESC-MSCs prevent the progression of fatal lupus nephritis (LN) in NZB/W F1 (BWF1) mice. Treatment led to statistically significant reductions in proteinuria and serum creatinine and preserved renal architecture. Specifically, hESC-MSC treatment prevented disease-associated interstitial inflammation, protein cast deposition and infiltration of CD3 + lymphocytes in the kidneys. This therapy also led to significant reductions in serum levels of tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6), two inflammatory cytokines associated with SLE. Mechanistically, in vitro data support these findings, as co-culture of hESC-MSCs with lipopolysaccharide (LPS)-stimulated BWF1 lymphocytes decreased lymphocyte secretion of TNFα and IL-6 and enhanced the percentage of putative regulatory T cells. This study represents an important step in the development of a commercially scalable and efficacious cell therapy for SLE/LN.