Cellular Immunotherapy for Septic Shock. A Phase I Clinical Trial

McIntyre, Lauralyn; Stewart, Duncan J.; Mei, Shirley H. J.; Courtman, David W.; Watpool, Irene; Granton, John; Marshall, John C.; Santos, Claudia C. dos; Walley, Keith R.; Winston, Brent W.; Fergusson, Dean

doi:10.1164/rccm.201705-1006oc

Cited by 122 publications

(115 citation statements)

References 47 publications

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“…However, the clinical study of the team of Garcia-Sancho (34) showed that better HLA matching of donor MSCs with recipients did not enhance the efficacy of MSCs therapy in osteoarthritis and degenerative disc disease. Furthermore, there are several completed clinical trials applying allogenic MSC without any analysis of donor MSCs and recipient matching (5,(35)(36)(37) indicating that the donor MSCs and recipient matching may not play the role in MSCs potency. This direction is further supported by tendencies to apply pooled MSCs batches as better available and reproducible source of MSCs (38).…”

Section: Discussionmentioning

confidence: 99%

“…In MSC-CONTROL and MSC-SEPSIS groups, MCSs were infused in a clinically relevant dose (1 × 10 6 /kg) over 10 min via the central venous line 6 h from the baseline. The MSC dose was chosen on the basis of several previous clinical (5,6) as well as experimental rodent (1,2) and large animal studies (7). At the end of the experiment, the animals were euthanized by anesthetic overdose and excision of the heart.…”

Section: Experimental Protocolmentioning

confidence: 99%

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Evaluation of Mesenchymal Stem Cell Therapy for Sepsis: A Randomized Controlled Porcine Study

et al. 2020

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Background: Treatment with mesenchymal stem cells (MSCs) has elicited considerable interest as an adjunctive therapy in sepsis. However, the encouraging effects of experiments with MSC in rodents have not been adequately studied in large-animal models with better relevance to human sepsis. Objectives: Here, we aimed to assess safety and efficacy of bone marrow-derived MSCs in a clinically relevant porcine model of progressive peritonitis-induced sepsis. Methods: Thirty-two anesthetized, mechanically ventilated, and instrumented pigs were randomly assigned into four groups (n = 8 per group): (1) sham-operated group (CONTROL); (2) sham-operated group treated with MSCs (MSC-CONTROL); (3) sepsis group with standard supportive care (SEPSIS); and (4) sepsis group treated with MSCs (MSC-SEPSIS). Peritoneal sepsis was induced by inoculating cultivated autologous feces. MSCs (1 × 10 6 /kg) were administered intravenously at 6 h after sepsis induction. Results: Before, 12, 18, and 24 h after the induction of peritonitis, we measured systemic, regional, and microvascular hemodynamics, multiple-organ functions, mitochondrial energy metabolism, systemic immune-inflammatory response, and oxidative stress. Administration of MSCs in the MSC-CONTROL group did not elicit any measurable acute effects. Treatment of septic animals with MSCs failed to mitigate sepsis-induced hemodynamic alterations or the gradual rise in Sepsis-related organ failure assessment scores. MSCs did not confer any protection against sepsis-mediated cellular myocardial depression and mitochondrial dysfunction. MSCs also failed to modulate the deregulated immune-inflammatory response. Horak et al. Stem Cell Therapy for Sepsis Conclusion: Intravenous administration of bone marrow-derived MSCs to healthy animals was well-tolerated. However, in this large-animal, clinically relevant peritonitis-induced sepsis model, MSCs were not capable of reversing any of the sepsis-induced disturbances in multiple biological, organ, and cellular systems.

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Section: Discussionmentioning

confidence: 99%

Section: Experimental Protocolmentioning

confidence: 99%

Evaluation of Mesenchymal Stem Cell Therapy for Sepsis: A Randomized Controlled Porcine Study

et al. 2020

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“…These results, combined with previous reports from other groups, suggest that a uniform expression pattern for MSCs that excludes contaminating cell types may vary depending on the sensitivity of methodologies used. Multiple studies have provided evidence that MSCs possess immunomodulatory functions . Within our proteomic analyses, we identified both a secretory and phenotypic expression patterns associated with immunomodulation or inflammation.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a Vimentinhigh/Nestinhigh proteome and tissue regenerative secretome generated by human pancreas-derived mesenchymal stromal cells

Cooper

Sherman

Bell³

et al. 2020

Stem Cells

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Multipotent/mesenchymal stromal cells (MSCs) exist within a variety of postnatal tissues; however, global proteomic analyses comparing tissue-specific MSC are limited. Using human bone marrow (BM)-derived MSCs as a gold standard, we used label-free mass spectrometry and functional assays to characterize the proteome, secretome, and corresponding function of human pancreas-derived MSCs (Panc-MSCs) with a classical phenotype (CD90+/CD73+/CD105+/CD45−/CD31−). Both MSC subtypes expressed mesenchymal markers vimentin, α-SMA, and STRO-1; however, expression of nestin was increased in Panc-MSCs. Accordingly, these Vimentin high /Nestin high cells were isolated from fresh human pancreatic islet and non-islet tissues. Next, we identified expression of >60 CD markers shared between Panc-MSCs and BM-MSCs, including validated expression of CD14. An additional 19 CD markers were differentially expressed, including reduced pericyte-marker CD146 expression on Panc-MSCs. Panc-MSCs also showed reduced expression of proteins involved in lipid and retinoid metabolism. Accordingly, Panc-MSCs showed restricted responses to adipogenic stimuli in vitro, although both MSC types demonstrated trilineage differentiation. In contrast, Panc-MSCs demonstrated accelerated growth kinetics and competency to proneurogenic stimuli in vitro. The secretome of Panc-MSCs was highly enriched for proteins associated with vascular development, wound healing and chemotaxis. Similar to BM-MSCs, Panc-MSCs conditioned media augmented endothelial cell survival, proliferation, and tubule formation in vitro. Importantly, the secretome of both MSC types was capable of stimulating chemotactic infiltration of murine endothelial cells in vivo and reduced hyperglycemia in STZ-treated mice following intrapancreatic injection. Overall, this study provides foundational knowledge to develop Panc-MSCs as a unique MSC subtype with functional properties beneficial in regenerative medicine for diabetes and vascular disease. K E Y W O R D S adipogenesis, multipotent stromal cells, nestin, pancreas, proteomics, regenerative medicine, secretome

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“…7 The development of serum-free conditions appears encouraging for translation of MSC-based therapies, and numerous clinical trials of MSCs for regenerative therapy and immune modulation have been conducted using approved media and other reagents. 8 Heterogeneity, however, in the source of MSCs, dosing, administration schedules, and outcome reporting continues to hamper definitive conclusions regarding the efficacy of MSCs in certain indications such as graft-versus-host disease (GVHD). 9 The observation that conditioned media from MSCs retains much of the therapeutic effects of MSCs themselves has contributed to the development and interest in MSC-derived small EVs as a therapeutic tool, highlighted by initial studies in acute kidney injury 10 and myocardial ischemia/reperfusion injury.…”

Section: Starting Materialsmentioning

confidence: 99%

Mesenchymal stromal cell-derived extracellular vesicles for regenerative therapy and immune modulation: Progress and challenges toward clinical application

Allan

Tieu

Lalu

et al. 2019

Stem Cells Translational Medicine

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Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have emerged as a promising form of regenerative therapy and immune modulation. Fundamental advances in our understanding of MSCs and EVs have allowed these fields to merge and create potential cell-free therapy options that are cell-based. EVs contain active cargo including proteins, microRNA, and mRNA species that can impact signaling responses in target cells to modify inflammatory and repair responses. Increasing numbers of preclinical studies in animals with various types of injury models have been published that demonstrate the potential impact of MSC-EV therapy. Although the emergence of registered clinical protocols suggests translation to clinical application has already begun, several barriers to more widespread clinical adoption remain. In this review, we highlight the progress made in MSC-derived small EV-based therapy by summarizing aspects pertaining to the starting material for MSC expansion, EV production, and isolation methods, studies from preclinical models that have established a foundation of knowledge to support translation into the patient setting, and potential barriers to overcome on the path to clinical application. K E Y W O R D S extracellular vesicles, immune modulation, mesenchymal stromal cells, preclinical, regenerative therapy

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Cellular Immunotherapy for Septic Shock. A Phase I Clinical Trial

Abstract: The infusion of freshly cultured allogenic bone marrow-derived MSCs, up to a dose of 3 million cells/kg (250 million cells), into participants with septic shock seems safe. Clinical trial registered with www.clinicaltrials.gov (NCT02421484).

Cited by 122 publications

References 47 publications

Evaluation of Mesenchymal Stem Cell Therapy for Sepsis: A Randomized Controlled Porcine Study

Evaluation of Mesenchymal Stem Cell Therapy for Sepsis: A Randomized Controlled Porcine Study

Characterization of a Vimentinhigh/Nestinhigh proteome and tissue regenerative secretome generated by human pancreas-derived mesenchymal stromal cells

Mesenchymal stromal cell-derived extracellular vesicles for regenerative therapy and immune modulation: Progress and challenges toward clinical application

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