Abstract
SummaryMesenchymal stromal cells (MSCs) ameliorate pre-clinical sepsis and sepsis-associated acute kidney injury (SA-AKI) but clinical trials of single-dose MSCs have not indicated robust efficacy. This study investigated immunomodulatory effects of a novel MSC product (CD362-selected human umbilical cord-derived MSCs [hUC-MSCs]) in mouse endotoxemia and polymicrobial sepsis models. Initially, mice received intra-peritoneal (i.p.) lipopolysaccharide (LPS) followed by single i.p. doses of hUC-MSCs or vehicle. Next, mice underwent cecal ligation and puncture (CLP) followed by intravenous (i.v.) doses of hUC-MSCs at 4 h or 4 and 28 h. Analyses included serum/plasma assays of biochemical indices, inflammatory mediators and the AKI biomarker NGAL; multi-color flow cytometry of peritoneal macrophages (LPS) and intra-renal immune cell subpopulations (CLP) and histology/immunohistochemistry of kidney (CLP). At 72 h post-LPS injections, hUC-MSCs reduced serum inflammatory mediators and peritoneal macrophage M1/M2 ratio. Repeated, but not single, hUC-MSC doses administered at 48 h post-CLP resulted in lower serum concentrations of inflammatory mediators, lower plasma NGAL and reversal of sepsis-associated depletion of intra-renal T cell and myeloid cell subpopulations. Hierarchical clustering analysis of all 48-h serum/plasma analytes demonstrated partial co-clustering of repeated-dose hUC-MSC CLP animals with a Sham group but did not reveal a distinct signature of response to therapy. It was concluded that repeated doses of CD362-selected hUC-MSCs are required to modulate systemic and local immune/inflammatory events in polymicrobial sepsis and SA-AKI. Inter-individual variability and lack of effect of single dose MSC administration in the CLP model are consistent with observations to date from early-phase clinical trials.Graphical
Highlights
Sepsis is characterised by life-threatening organ dysfunction due to a dysregulated host response to infection caused by bacterial, fungal, viral, and parasitic pathogens [1]
We aimed to demonstrate the anti-inflammatory potential of single doses of hUC-Mesenchymal stromal cells (MSCs) in mouse models of LPS- and CLPinduced endotoxemia/polymicrobial sepsis [25, 26] and, in the latter, to determine whether a second administration of human umbilical cord-derived MSC (hUC-MSC) during the early disease course resulted in greater or more frequent beneficial effects on systemic inflammation and organ-specific injury, exemplified by SA-acute kidney injury (AKI)
Peritoneal macrophages from hUC-MSC-treated animals had lower CD68 surface expression and lower CD68/CD206 ratio compared to those from saline-treated animals. These results demonstrated that a single dose of hUC-MSC had distinct anti-inflammatory and immune-modulatory effects in a simplified sepsis-like model with limited influence on overall disease severity
Summary
Sepsis is characterised by life-threatening organ dysfunction due to a dysregulated host response to infection caused by bacterial, fungal, viral, and parasitic pathogens [1]. Administration of allogeneic MSC to patients with septic shock (NCT01849237, NCT02421484, and NCT02328612) and sepsis-related acute respiratory distress syndrome (NCT01775774) demonstrated good safety and tolerability in Phase 1 clinical trials [16,17,18,19]. Despite these encouraging results, Galstyan et al reported that a single dose of i.v. MSC did not prevent death from sepsis-related organ dysfunction, raising the possibility that additional doses may be necessary to derive meaningful clinical benefit [17]. Incomplete knowledge of the mechanism of action, dose response and optimal clinical indices for MSC administration in sepsis limits the potential for designing successful trials [5, 21, 22]
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