title: Human embryonic stem cell-derived mesenchymal cells preserve kidney function and extend lifespan in NZB/W F1 mouse model of lupus nephritis.
abstract: 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.
authors.affiliation: Ocata Therapeutics, Marlborough, MA 01752.
authors.forename: Austin
authors.initials: A
authors.lastname: Thiel
authors.affiliation: Ocata Therapeutics, Marlborough, MA 01752.
authors.forename: Gregory
authors.initials: G
authors.lastname: Yavanian
authors.affiliation: Ocata Therapeutics, Marlborough, MA 01752.
authors.forename: Maria-Dorothea
authors.initials: MD
authors.lastname: Nastke
authors.affiliation: Ocata Therapeutics, Marlborough, MA 01752.
authors.forename: Peter
authors.initials: P
authors.lastname: Morales
authors.affiliation: Ocata Therapeutics, Marlborough, MA 01752.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Kouris
authors.affiliation: Ocata Therapeutics, Marlborough, MA 01752.
authors.forename: Erin A
authors.initials: EA
authors.lastname: Kimbrel
authors.affiliation: Ocata Therapeutics, Marlborough, MA 01752.
authors.forename: Robert
authors.initials: R
authors.lastname: Lanza
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D064593:Heterografts; D000066449:Human Embryonic Stem Cells / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008181:Lupus Nephritis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice