scholarly journals Methods and efficacy of extracellular vesicles derived from mesenchymal stromal cells in animal models of disease: a preclinical systematic review protocol

2019 ◽  
Vol 8 (1) ◽  
Author(s):  
Alvin Tieu ◽  
Mitchell Slobodian ◽  
Dean A. Fergusson ◽  
Joshua Montroy ◽  
Dylan Burger ◽  
...  
Keyword(s):  
Systematic Review ◽  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Mesenchymal Stromal Cell ◽  
Stromal Cell ◽  
Extracellular Vesicle ◽  
Preclinical Studies ◽  
Tissue Source ◽  
Models Of Disease

Abstract Background Over the past decade, mesenchymal stromal cells have been increasingly investigated for their therapeutic potential in several different illnesses. However, cell therapy can be limited by potentially serious adverse events including cell embolus formation and tumorigenesis. Importantly, the protective effects of mesenchymal stromal cells are largely mediated by paracrine mechanisms including release of extracellular vesicles. This systematic review intends to synthesize the current knowledge of mesenchymal stromal cell-derived extracellular vesicles as a therapeutic option for preclinical models of disease, inflammation, or injury. Methods A systematic literature search of MEDLINE, Embase, and BIOSIS databases will be conducted. Interventional preclinical in vivo studies using extracellular vesicles derived from any tissue source of mesenchymal stromal cells will be included. Studies will be screened by abstract, and full-text by two independent reviewers. Eligible studies will undergo data extraction with subcategorization into domains based on disease. Methods utilized for extracellular vesicle characterization and isolation will be collected, as well as information on interventional traits, such as tissue source of mesenchymal stromal cells, dosage regimen, and vesicle modifications. Reported outcomes will be collected to determine which diseases studied may be impacted most from treatment with mesenchymal stromal cell-derived extracellular vesicles. Discussion This systematic review will summarize preclinical studies investigating the therapeutic efficacy of both small and large extracellular vesicles derived by mesenchymal stromal cells. Extracellular vesicles represent a possibility to harness the benefits of mesenchymal stromal cells with added benefits of reduced manufacturing costs and an improved safety profile. Hence, there has been an exponential increase in interest for developing this cell-free therapy with hundreds of preclinical studies published to date. However, a vast amount of heterogeneity between groups relates to methods of extracellular vesicle isolation, characterization, and study design. This review will capture this heterogeneity and identify the most commonly used and optimal approaches to evaluate mesenchymal stromal cell-derived extracellular vesicle treatment. A meta-analysis of outcomes within each disease domain will help elucidate which fields of research demonstrate promise for developing extracellular vesicles as a novel cell-free therapy. Summarizing this robust information on extracellular vesicles as an intervention can provide guidance for designing preclinical studies with hopes of future clinical translation.

scholarly journals Clinical Translation of Mesenchymal Stromal Cell Therapies in Nephrology

2017 ◽  
Vol 29 (2) ◽  
pp. 362-375 ◽  
Author(s):  
Norberto Perico ◽  
Federica Casiraghi ◽  
Giuseppe Remuzzi
Keyword(s):  
Organ Transplantation ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Mesenchymal Stromal Cell ◽  
Stromal Cell ◽  
Solid Organ ◽  
Preclinical Studies ◽  
Chronic Injury ◽  
Cell Therapies ◽  
Cell Based Therapy

Mesenchymal stromal cells have emerged as potential candidates for cell-based therapies to modulate the immune response in organ transplantation and repair tissues after acute or chronic injury. Preclinical studies have shown convincingly in rodent models that mesenchymal stromal cells can prolong solid organ graft survival and that they can induce immune tolerance, accelerate recovery from AKI, and promote functional improvement in chronic nephropathies. Multiple complex properties of the cells, including immunomodulatory, anti-inflammatory, and proregenerative effects, seem to contribute. The promising preclinical studies have encouraged investigators to explore the safety, tolerability, and efficacy of mesenchymal stromal cell–based therapy in pilot clinical trials, including those for bone marrow and solid organ transplantation, autoimmune diseases, and tissue and organ repair. Here, we review the available data on culture-expanded mesenchymal stromal cells tested in renal transplantation, AKI, and CKD. We also briefly discuss the relevant issues that must be addressed to ensure rigorous assessment of the safety and efficacy of mesenchymal stromal cell therapies to allow the translation of this research into the practice of clinical nephrology.

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.

Loss of TGF-β Signaling in Bone Marrow Mesenchymal Progenitors Promotes Adipocyte over Osteoblast Differentiation but Does Not Disrupt the HSC Niche

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 666-666
Author(s):  
Grazia Abou Ezzi ◽  
Teerawit Suparkorndej ◽  
Bryan Anthony ◽  
Jingzhu Zhang ◽  
Shilpi Ganguly ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Mesenchymal Stromal Cell ◽  
Stromal Cell ◽  
Transforming Growth Factor ◽  
Cell Populations ◽  
Mesenchymal Progenitors ◽  
Hsc Niche

Abstract Hematopoietic stem cells (HSCs) reside in specialized microenvironments (niches) in the bone marrow. Several mesenchymal stromal cells have been implicated in hematopoietic niches, including osteoblasts, pericytes, CXCL12-abundant reticular (CAR) cells, and mesenchymal stem cells (MSCs). Members of the transforming growth factor (TGF) superfamily, in particular TGF-β, have a well-documented role in regulating osteoblast development. However, the contribution of TGF family member signaling to the establishment and maintenance of hematopoietic niches is largely unknown. Here, we characterize the role of transforming growth factor-β (TGF-β) signaling in mesenchymal stromal cells on the HSC niche. TGF-β receptor 2 (encoded by Tgfbr2) is required for all TGF-β signaling. To selectively disrupt TGF-β signaling in bone marrow mesenchymal stromal cells, we generated Osx-C re Tgfbr2fl/fl mice. Osx-Cre targets most bone marrow mesenchymal stromal cells (including osteoblasts, CAR cells, MSCs, pericytes, and adipocytes) but not endothelial cells or hematopoietic cells. Osx-C re Tgfbr2fl/fl mice are severely runted and most die by 4 weeks of age. We analyzed mice at 3 weeks, when the mice appeared healthy. Osteoblast number was severely reduced in Osx-C re Tgfbr2fl/fl mice, as assessed by histomorphometry and immunostaining for osteocalcin. Accordingly, microCT analysis demonstrated reduced tissue mineral density and cortical thickness of long bone and marked trabecularization of long bones in diaphyseal regions. Surprisingly, marrow adiposity, as measured by osmium tetroxide staining with microCT, was strikingly increased in Osx-C re Tgfbr2fl/fl mice. CAR cells are mesenchymal progenitors with osteogenic and adipogenic potential in vitro. To assess CAR cells, we generated Osx-Cre Tgfrb2fl/fl x Cxcl12gfp mice. Surprisingly, CAR cell number was significantly increased. However, despite the increase in CAR cells, the number of CFU-osteoblast (CFU-OB) in Osx-C re Tgfbr2fl/fl mice is nearly undetectable. Together, these data suggest that TGF-b signaling contributes to lineage commitment of mesenchymal progenitors. Specifically, our data suggest that TGF-β signaling suppresses commitment to the osteoblast lineage, while increasing adipogenic differentiation. We next asked whether alterations in bone marrow stromal cells present in Osx-C re Tgfbr2fl/fl mice affect HSC number or function. The increase in marrow adipocytes and loss of osteolineage cells is predicted to impair HSC maintenance, while the increase in CAR cells might augment HSCs. Osx-Cre Tgfrb2fl/fl mice have modest leukopenia, but normal red blood cell and platelet counts. Bone marrow and spleen cellularity are reduced, even after normalizing for body weight. The frequency of phenotypic HSCs (defined as Kit+ lineage- Sca+ CD34- Flk2- cells) is comparable to control mice. To assess HSC function, we performed competitive repopulation assays with bone marrow from Osx-Cre Tgfrb2fl/fl or control mice. Surprisingly, these data show that the long-term multi-lineage repopulating activity of HSCs from Osx-Cre Tgfrb2fl/fl mice is normal. Moreover, serial transplantation studies suggest that the self-renewal capacity of HSCs is normal. Thus, despite major alterations in mesenchymal stromal cell populations, the HSC niche is intact in Osx-Cre Tgfrb2fl/fl mice. Collectively, these data show that TGF-b signaling in mesenchymal progenitors is required for the proper development of multiple stromal cell populations that contribute to hematopoietic niches. Studies are underway to assess the impact of post-natal deletion of Tgfbr2 in mesenchymal stromal cell on hematopoietic niches. Since drugs that modulate the activity of TGF-b are in development, this research may suggest novel approaches to modulate hematopoietic niches for therapeutic benefit. Disclosures No relevant conflicts of interest to declare.

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.

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