scholarly journals Human Umbilical Cord Mesenchymal Stromal Cells Attenuate Systemic Sepsis in Part by Enhancing Peritoneal Macrophage Bacterial Killing via Heme Oxygenase-1 Induction in Rats

2020 ◽  
Vol 132 (1) ◽  
pp. 140-154 ◽  
Author(s):  
Mirjana Jerkic ◽  
Stéphane Gagnon ◽  
Razieh Rabani ◽  
Taylor Ward-Able ◽  
Claire Masterson ◽  
...  
Keyword(s):  
Umbilical Cord ◽  
Heme Oxygenase ◽  
Mesenchymal Stromal Cells ◽  
Dose Response ◽  
Stromal Cells ◽  
Mesenchymal Stromal Cell ◽  
Stromal Cell ◽  
Heme Oxygenase 1 ◽  
Human Umbilical Cord ◽  
Bacterial Killing

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Mesenchymal stromal cells have therapeutic potential in sepsis, but the mechanism of action is unclear. We tested the effects, dose-response, and mechanisms of action of cryopreserved, xenogeneic-free human umbilical cord mesenchymal stromal cells in a rat model of fecal peritonitis, and examined the role of heme oxygenase-1 in protection. Methods Separate in vivo experiments evaluated mesenchymal stromal cells in fecal sepsis, established dose response (2, 5, and 10 million cells/kg), and the role of heme oxygenase-1 in mediating human umbilical cord–derived mesenchymal stromal/stem cell effects. Ex vivo studies utilized pharmacologic blockers and small inhibitory RNAs to evaluate mechanisms of mesenchymal stromal cell enhanced function in (rodent, healthy and septic human) macrophages. Results Human umbilical cord mesenchymal stromal cells reduced injury and increased survival (from 48%, 12 of 25 to 88%, 14 of 16, P = 0.0033) in fecal sepsis, with dose response studies demonstrating that 10 million cells/kg was the most effective dose. Mesenchymal stromal cells reduced bacterial load and peritoneal leukocyte infiltration (from 9.9 ± 3.1 × 106/ml to 6.2 ± 1.8 × 106/ml, N = 8 to 10 per group, P < 0.0001), and increased heme oxygenase-1 expression in peritoneal macrophages, liver, and spleen. Heme oxygenase-1 blockade abolished the effects of mesenchymal stromal cells (N = 7 or 8 per group). Mesenchymal stromal cells also increased heme oxygenase-1 expression in macrophages from healthy donors and septic patients. Direct ex vivo upregulation of macrophage heme oxygenase-1 enhanced macrophage function (phagocytosis, reactive oxygen species production, bacterial killing). Blockade of lipoxin A4 production in mesenchymal stromal cells, and of prostaglandin E2 synthesis in mesenchymal stromal cell/macrophage cocultures, prevented upregulation of heme oxygenase-1 in macrophages (from 9.6 ± 5.5-fold to 2.3 ± 1.3 and 2.4 ± 2.3 respectively, P = 0.004). Knockdown of heme oxygenase-1 production in macrophages ablated mesenchymal stromal cell enhancement of macrophage phagocytosis. Conclusions Human umbilical cord mesenchymal stromal cells attenuate systemic sepsis by enhancing peritoneal macrophage bacterial killing, mediated partly via upregulation of peritoneal macrophage heme oxygenase-1. Lipoxin A4 and prostaglandin E2 play key roles in the mesenchymal stromal cell and macrophage interaction.

scholarly journals Extracellular Vesicles from Interferon-γ–primed Human Umbilical Cord Mesenchymal Stromal Cells Reduce Escherichia coli–induced Acute Lung Injury in Rats

2019 ◽  
Vol 130 (5) ◽  
pp. 778-790 ◽  
Author(s):  
Amir K. Varkouhi ◽  
Mirjana Jerkic ◽  
Lindsay Ormesher ◽  
Stéphane Gagnon ◽  
Sakshi Goyal ◽  
...  
Keyword(s):  
Umbilical Cord ◽  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Mesenchymal Stromal Cell ◽  
Stromal Cell ◽  
Interferon Γ ◽  
Human Umbilical Cord ◽  
E Coli

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Human umbilical cord mesenchymal stromal cells possess considerable therapeutic promise for acute respiratory distress syndrome. Umbilical cord mesenchymal stromal cells may exert therapeutic effects via extracellular vesicles, while priming umbilical cord mesenchymal stromal cells may further enhance their effect. The authors investigated whether interferon-γ–primed umbilical cord mesenchymal stromal cells would generate mesenchymal stromal cell–derived extracellular vesicles with enhanced effects in Escherichia coli (E. coli) pneumonia. Methods In a university laboratory, anesthetized adult male Sprague–Dawley rats (n = 8 to 18 per group) underwent intrapulmonary E. coli instillation (5 × 109 colony forming units per kilogram), and were randomized to receive (a) primed mesenchymal stromal cell–derived extracellular vesicles, (b) naïve mesenchymal stromal cell–derived extracellular vesicles (both 100 million mesenchymal stromal cell–derived extracellular vesicles per kilogram), or (c) vehicle. Injury severity and bacterial load were assessed at 48 h. In vitro studies assessed the potential for primed and naïve mesenchymal stromal cell–derived extracellular vesicles to enhance macrophage bacterial phagocytosis and killing. Results Survival increased with primed (10 of 11 [91%]) and naïve (8 of 8 [100%]) mesenchymal stromal cell–derived extracellular vesicles compared with vehicle (12 of 18 [66.7%], P = 0.038). Primed—but not naïve—mesenchymal stromal cell–derived extracellular vesicles reduced alveolar–arterial oxygen gradient (422 ± 104, 536 ± 58, 523 ± 68 mm Hg, respectively; P = 0.008), reduced alveolar protein leak (0.7 ± 0.3, 1.4 ± 0.4, 1.5 ± 0.7 mg/ml, respectively; P = 0.003), increased lung mononuclear phagocytes (23.2 ± 6.3, 21.7 ± 5, 16.7 ± 5 respectively; P = 0.025), and reduced alveolar tumor necrosis factor alpha concentrations (29 ± 14.5, 35 ± 12.3, 47.2 ± 6.3 pg/ml, respectively; P = 0.026) compared with vehicle. Primed—but not naïve—mesenchymal stromal cell–derived extracellular vesicles enhanced endothelial nitric oxide synthase production in the injured lung (endothelial nitric oxide synthase/β-actin = 0.77 ± 0.34, 0.25 ± 0.29, 0.21 ± 0.33, respectively; P = 0.005). Both primed and naïve mesenchymal stromal cell–derived extracellular vesicles enhanced E. coli phagocytosis and bacterial killing in human acute monocytic leukemia cell line (THP-1) in vitro (36.9 ± 4, 13.3 ± 8, 0.1 ± 0.01%, respectively; P = 0.0004) compared with vehicle. Conclusions Extracellular vesicles from interferon-γ–primed human umbilical cord mesenchymal stromal cells more effectively attenuated E. coli–induced lung injury compared with extracellular vesicles from naïve mesenchymal stromal cells, potentially via enhanced macrophage phagocytosis and killing of E. coli.

scholarly journals Intravenous Human Umbilical Cord-Derived Mesenchymal Stromal Cell Administration in Models of Moderate and Severe Intracerebral Hemorrhage

2020 ◽  
Vol 29 (9) ◽  
pp. 586-598 ◽  
Author(s):  
Tanira Giara Mello ◽  
Paulo Henrique Rosado-de-Castro ◽  
Raquel Maria Pereira Campos ◽  
Juliana Ferreira Vasques ◽  
William Simões Rangel-Junior ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Umbilical Cord ◽  
Mesenchymal Stromal Cell ◽  
Stromal Cell ◽  
Human Umbilical Cord

scholarly journals Therapeutic effect of human umbilical cord-derived multipotent mesenchymal stromal cells in a patient with Crigler–Najjar syndrome type I

2019 ◽  
Vol 64 (4) ◽  
pp. 26-34
Author(s):  
G. T. Sukhikh ◽  
A. V. Degtyareva ◽  
D. N. Silachev ◽  
K. V. Gorunov ◽  
I. V. Dubrovina ◽  
...  
Keyword(s):  
Umbilical Cord ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Multipotent Mesenchymal Stromal Cells ◽  
Human Umbilical Cord ◽  
Type I ◽  
Syndrome Type ◽  
Safe Level ◽  
Period 2

The article presents the results of intravenous transplantation of allogeneic multipotent mesenchymal stromal cells, derived from a human umbilical cord, to a child with Crigler–Najjarsyndrome type I during the first 2 years of life. The therapy is aimed at reduction of the duration of phototherapy while maintaining a safe level of serum bilirubin.In this study, a five-day-old child with the bilirubin level of 340 µmol/l was treated with phototherapy for 16–18 hours daily in the neonatal period. Then, phototherapy was reduced to 14–16 hours. The level of bilirubin varied from 329 to 407 μmol/l. At the age of 2 months, it was decided to use multipotent mesenchymal stromal cells with a significant decrease in the duration of phototherapy up to 2 hours a day. During the observation period (2 years at the time of writing this article) the child received 6 injections of multipotent mesenchymal stromal cells. A positive effect developed within 4–7 days after administration and persisted for 2–3 months. There were no side effects or complications during and after transplantation.Thus, intravenous transplantation of multipotent mesenchymal stromal cells is an effective treatment of Crigler–Najjar syndrome type I; it reducesthe need for phototherapy,significantly improvesthe quality of life of the patients and prolongstheir life with native liver. 

High yield of human umbilical cord-derived mesenchymal stromal cells in an animal component-free culture medium

Cytotherapy ◽  
2020 ◽  
Vol 22 (5) ◽  
pp. S111-S112
Author(s):  
R. Wagey ◽  
K. Bertram ◽  
M. Elliott ◽  
A. Eaves ◽  
S. Szilvassy ◽  
...  
Keyword(s):  
Umbilical Cord ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Culture Medium ◽  
High Yield ◽  
Human Umbilical Cord ◽  
Animal Component

scholarly journals Umbilical cord as a long-term source of activatable mesenchymal stromal cells for immunomodulation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Anton Selich ◽  
Katharina Zimmermann ◽  
Michel Tenspolde ◽  
Oliver Dittrich-Breiholz ◽  
Constantin von Kaisenberg ◽  
...  
Keyword(s):  
Umbilical Cord ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Induction Time ◽  
Dna Barcode ◽  
Human Umbilical Cord ◽  
Time Points

Abstract Background Mesenchymal stromal cells (MSCs) are used in over 800 clinical trials mainly due to their immune inhibitory activity. Umbilical cord (UC), the second leading source of clinically used MSCs, is usually cut in small tissue pieces. Subsequent cultivation leads to a continuous outgrowth of MSC explant monolayers (MSC-EMs) for months. Currently, the first MSC-EM culture takes approximately 2 weeks to grow out, which is then expanded and applied to patients. The initiating tissue pieces are then discarded. However, when UC pieces are transferred to new culture dishes, MSC-EMs continue to grow out. In case the functional integrity of these cells is maintained, later induced cultures could also be expanded and used for cell therapy. This would drastically increase the number of available cells for each patient. To test the functionality of MSC-EMs from early and late induction time points, we compared the first cultures to those initiated after 2 months by investigating their clonality and immunomodulatory capacity. Methods We analyzed the clonal composition of MSC-EM cultures by umbilical cord piece transduction using integrating lentiviral vectors harboring genetic barcodes assessed by high-throughput sequencing. We investigated the transcriptome of these cultures by microarrays. Finally, the secretome was analyzed by multiplexed ELISAs, in vitro assays, and in vivo in mice. Results DNA barcode analysis showed polyclonal MSC-EMs even after months of induction cycles. A transcriptome and secretome analyses of early and late MSC cultures showed only minor changes over time. However, upon activation with TNF-α and IFN-γ, cells from both induction time points produced a multitude of immunomodulatory cytokines. Interestingly, the later induced MSC-EMs produced higher amounts of cytokines. To test whether the different cytokine levels were in a therapeutically relevant range, we used conditioned medium (CM) in an in vitro MLR and an in vivo killing assay. CM from late induced MSC-EMs was at least as immune inhibitory as CM from early induced MSC-EMs. Conclusion Human umbilical cord maintains a microenvironment for the long-term induction of polyclonal and immune inhibitory active MSCs for months. Thus, our results would offer the possibility to drastically increase the number of therapeutically applicable MSCs for a substantial amount of patients.

scholarly journals Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stromal Cells Protect Cardiac Cells Against Hypoxia/Reoxygenation Injury by Inhibiting Endoplasmic Reticulum Stress via Activation of the PI3K/Akt Pathway

2020 ◽  
Vol 29 ◽  
pp. 096368972094567
Author(s):  
Changyi Zhang ◽  
Hongwu Wang ◽  
Godfrey C.F. Chan ◽  
Yu Zhou ◽  
Xiulan Lai ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Umbilical Cord ◽  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Cardiac Cells ◽  
Akt Pathway ◽  
Human Umbilical Cord ◽  
Hypoxia Reoxygenation

Endoplasmic reticulum (ER) stress is implicated in the pathogenesis of many diseases, including myocardial ischemia/reperfusion injury. We hypothesized that human umbilical cord mesenchymal stromal cells derived extracellular vesicles (HuMSC-EVs) could protect cardiac cells against hyperactive ER stress induced by hypoxia/reoxygenation (H/R) injury. The H/R model was generated using the H9c2 cultured cardiac cell line. HuMSC-EVs were extracted using a commercially available exosome isolation reagent. Levels of apoptosis-related signaling molecules and the degree of ER stress were assessed by western blot. The role of the PI3K/Akt pathway was investigated using signaling inhibitors. Lactate dehydrogenase leakage and 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) analysis were used for evaluating the therapeutic effects of HuMSC-EVs in vitro. The results showed that ER stress and the rate of apoptosis were increased in the context of H/R injury. Treatment with HuMSC-EVs inhibited ER stress and increased survival in H9c2 cells exposed to H/R. Mechanistically, the PI3K/Akt pathway was activated by treatment with HuMSC-EVs after H/R. Inhibition of the PI3K/Akt pathway by a specific inhibitor, LY294002, partially reduced the protective effect of HuMSC-EVs. Our findings suggest that HuMSC-EVs could alleviate ER stress–induced apoptosis during H/R via activation of the PI3K/Akt pathway.

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