Umbilical Cord-Derived CD362+ Mesenchymal Stromal Cells Attenuate Polymicrobial Sepsis Induced by Caecal Ligation and Puncture

Abstract

Mesenchymal stromal cells (MSCs) have a multimodal, immunomodulatory mechanism of action and are now in clinical trials for single organ and systemic sepsis. However, a number of practicalities around source, homogeneity and therapeutic window remain to be determined. Here, we utilised conditioned medium from CD362+-sorted umbilical cord-human MSCs (UC-hMSCs) for a series of in vitro anti-inflammatory assays and the cryopreserved MSCs themselves in a severe (Series 1) or moderate (Series 2+3) caecal ligation and puncture (CLP) rodent model. Surviving animals were assessed at 48 h post injury induction. MSCs improved human lung, colonic and kidney epithelial cell survival following cytokine activation. In severe systemic sepsis, MSCs administered at 30 min enhanced survival (Series 1), and reduced organ bacterial load. In moderate systemic sepsis (Series 2), MSCs were ineffective when delivered immediately or 24 h later. Of importance, MSCs delivered 4 h post induction of moderate sepsis (Series 3) were effective, improving serum lactate, enhancing bacterial clearance from tissues, reducing pro-inflammatory cytokine concentrations and increasing antimicrobial peptides in serum. While demonstrating benefit and immunomodulation in systemic sepsis, therapeutic efficacy may be limited to a specific point of disease onset, and repeat dosing, MSC enhancement or other contingencies may be necessary.

Comparison of single and repeated dosing of anti-inflammatory human umbilical cord mesenchymal stromal cells in a mouse model of polymicrobial sepsis

“…administration of a distinctive human MSC therapeutic product (CD362-enriched hUC-MSC) in the mouse CLP model of polymicrobial sepsis. Initially, in keeping with recently-reported results for this same MSC product in rat models of bacterial pneumonia and sepsis (23,24), we con rmed the potential for early administration of hUC-MSC to modulate LPS-induced systemic in ammation in mice. In a mouse CLP model of polymicrobial sepsis, however, our results indicated that single doses of hUC-MSC administered i.v.…”

“…In the current study, we performed pre-clinical investigation of the anti-in ammatory effects of CD362selected human umbilical cord-derived MSC (hUC-MSC) in mouse models of sepsis. This surface markerselected hUC-MSC is a novel therapeutic product that has demonstrated evidence of e cacy in rat models of bacterial pneumonia and sepsis when administered early after disease onset (23,24). As a clinical-grade investigational medicinal product (IMP), hUC-MSC is currently undergoing phase I/II trial in patients with moderate to severe acute respiratory distress syndrome (ARDS) due to COVID-19 (NCT03042143).…”

Therapeutic Use of Mesenchymal Stromal Cells: The Need for Inclusive Characterization Guidelines to Accommodate All Tissue Sources and Species

“…Other markers, such as Stro-1, CD271, CD362, and ABCB5, are also considered as MSC markers by some researchers and even used for MSC flow sorting (Ning et al, 2011 ; Álvarez-Viejo et al, 2015 ; Ballikaya et al, 2020 ; Gonzalez et al, 2020 ). However, in our review we did not find these antibodies to be as available for other species or as well-demonstrated in the literature as CD29 and CD44.…”

Comparison of Single and Repeated Dosing of Anti-Inflammatory Human Umbilical Cord Mesenchymal Stromal Cells in a Mouse Model of Polymicrobial Sepsis

“…Nonetheless, analysis of serum/plasma and kidney tissue at 48 hours indicated signi cant systemic in ammation and renal injury response. These latter analyses provided the clearest evidence for a modulatory effect of the double-dose hUC-MSC regimen on the severity of polymicrobial sepsis when compared to single-dose administration which, in contrast to results recently reported in a rat CLP model (24), was indistinguishable from the saline-treated CLP group across all indices examined. In particular, the clinically-relevant AKI biomarker, NGAL, proved to be a valuable discriminator of sepsis severity and treatment effect in this model and may be an important biomarker for future clinical trials of cell therapies in sepsis and SA-AKI (29,35).…”