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.
Highlights
(Benlysta), a monoclonal antibody targeting B cell-activating factor, or BAFF, has been approved for the treatment of Systemic lupus erythematosus (SLE) in the last half-century[16]
HESC-mesenchymal stem/stromal cells (MSCs) treatment led to the preservation of kidney function as detected by a statistically significant reduction in proteinuria and serum creatinine levels, as well as a lower trend in blood urea nitrogen (BUN) levels compared to non-treated controls
Renal architecture was significantly preserved as hESC-MSC treatment prevented age-associated mesangioproliferation, crescent formation, interstitial inflammation and protein cast formation that occurs in BWF1 kidneys as LN progresses
Summary
(Benlysta), a monoclonal antibody targeting B cell-activating factor, or BAFF, has been approved for the treatment of SLE in the last half-century[16]. Patients were followed for up to 4 years, showing strong rates of survival and remission[27] These studies hint at the promise of using mesenchymal cells to treat SLE. MSC scalability and preservation of therapeutic functionality will become problematic for cells derived from adult tissues Evidence indicates that both the age of the donated tissue and extended in vitro culture can negatively affect MSC quality and their therapeutic effect. MSCs derived from adult tissues are not replenishable, and if not extensively expanded, must constantly be derived from different donors, contributing to inconsistencies in their clinical performance Given these issues, a renewable source of MSCs from young tissue would provide a more potent, consistent, and reliable MSC therapeutic product, one that would allow large scale manufacturing without the need for extended in vitro culture, preserving their therapeutic efficacy. We monitor BWF1 kidney function as a tractable read-out for autoimmune disease progression and use the BWF1 model to test the therapeutic effects of hESC-MSCs, a renewable cellular therapy, for SLE/LN
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