A Novel Cellular Therapy to Treat Pancreatic Pain in Experimental Chronic Pancreatitis Using Human Alpha-1 Antitrypsin Overexpressing Mesenchymal Stromal Cells.
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ABSTRACT:
SUBMITTER: Chow RP
PROVIDER: S-EPMC8615652 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Numerous clinical trials are utilizing mesenchymal stem cells (MSC) to treat critical limb ischemia, primarily for their ability to secrete signals that promote revascularization. These cells have demonstrated clinical safety, but their efficacy has been limited, possibly because these paracrine signals are secreted at subtherapeutic levels. In these studies the combination of cell and gene therapy was evaluated by engineering MSC with a lentivirus to overexpress vascular endothelial growth factor (VEGF). To achieve clinical compliance, the number of viral insertions was limited to 1-2 copies/cell and a constitutive promoter with demonstrated clinical safety was used. MSC/VEGF showed statistically significant increases in blood flow restoration as compared with sham controls, and more consistent improvements as compared with nontransduced MSC. Safety of MSC/VEGF was assessed in terms of genomic stability, rule-out tumorigenicity, and absence of edema or hemangiomas in vivo. In terms of retention, injected MSC/VEGF showed a steady decline over time, with a very small fraction of MSC/VEGF remaining for up to 4.5 months. Additional safety studies completed include absence of replication competent lentivirus, sterility tests, and absence of VSV-G viral envelope coding plasmid. These preclinical studies are directed toward a planned phase 1 clinical trial to treat critical limb ischemia.
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Project description:More than 6.5 million patients are burdened by the physical, cognitive, and psychosocial deficits associated with traumatic brain injury (TBI) in the U.S. Despite extensive efforts to develop neuroprotective therapies for this devastating disorder, there have been no successful outcomes in human clinical trials to date. Retrospective studies have shown that ?-adrenergic receptor blockers, specifically propranolol, significantly decrease mortality of TBI through mechanisms not yet fully elucidated but are thought to counterbalance a hyperadrenergic state resulting from a TBI. Conversely, cellular therapies have been shown to improve long-term behavior following TBI, likely by reducing inflammation. Given the nonredundancy in their therapeutic mechanisms, we hypothesized that a combination of acute propranolol followed by mesenchymal stem cells (MSCs) isolated from human bone marrow would have additive effects in treating a rodent model of TBI. We have found that the treatments are well-tolerated individually and in combination with no adverse events. MSCs decrease BBB permeability at 96 hours after injury, inhibit a significant accumulation of activated microglia/macrophage in the thalamic region of the brain both short and long term, and enhance neurogenesis short term. Propranolol decreases edema and reduces the number of fully activated microglia at 7 days and the number of semiactivated microglia at 120 days. Combinatory treatment improved cognitive and memory functions 120 days following TBI. Therefore, the results here suggest a new, efficacious sequential treatment for TBI may be achieved using the ?-blocker propranolol followed by MSC treatment.Despite continuous efforts, traumatic brain injury (TBI) remains the leading cause of death and disability worldwide in patients under the age of 44. In this study, an animal model of moderate-severe TBI was treated with an acute dose of propranolol followed by a delayed dose of human mesenchymal stem cells (MSCs), resulting in improved short- and long-term measurements. These results have direct translational application. They reinforce the inevitable clinical trial of MSCs to treat TBI by demonstrating, among other benefits, a notable decrease in chronic neuroinflammation. More importantly, these results demonstrate that MSCs and propranolol, which is increasingly being used clinically for TBI, are compatible treatments that improve overall outcome.
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Project description:Mesenchymal stromal cells (MSCs) can modulate inflammation and contribute to tissue regeneration and, thus, have emerged as a promising option for cell-based therapy. However, the ability of MSCs to migrate to injured tissues still needs to be improved. In this study, we investigated whether genetically engineered MSCs could exhibit increased migratory properties and improved therapeutic efficacy. Using a mouse model of contact hypersensitivity (CHS), chemokine gene expression screening revealed that CXCL13 changed most significantly in injured tissue. Unfortunately, MSCs hardly express the corresponding receptor, CXCR5. Thus, CXCR5-overexpressing MSCs (MSCCXCR5) were generated that retained their abilities of proliferation, differentiation, and immunomodulation. Furthermore, MSCCXCR5 showed significantly increased migrating ability toward CXCL13. Importantly, systemic infusion of MSCCXCR5 dramatically suppressed CHS in mice, as evidenced by decreased levels of inflammatory cell infiltration and pro-inflammatory cytokine production. Numerous MSCCXCR5 migrated into inflamed ears, localized with T cells, inhibited T cell proliferation, promoted T cell apoptosis, and suppressed the production of T cell-derived pro-inflammatory factors. Collectively, these findings demonstrate that CXCR5 overexpression increases the ability of MSCs to respond to migratory stimuli and highly intensifies their immunomodulatory effects in vivo. This strategy for enhancing targeted stem/progenitor cell homing may improve the efficacy of MSC-based therapies.
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Project description:The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy. PAPERFLICK:
| S-EPMC4177038 | biostudies-literature
Project description:Preclinical trials confirmed the potential of mesenchymal stromal cells (MSCs) to improve functional recovery after experimental stroke. Beneficial effects of MSCs are often attributed to their immunosuppressive/immunomodulatory functions. Surprisingly, the influence of MSCs on the immune system after stroke is poorly understood, but requires special consideration because cerebral ischemia is associated with stroke-induced immunodepression that predisposes to bacterial infections with increased mortality. In this study, we intravenously transplanted syngeneic murine bone marrow-derived MSCs (mMSCs) into C57BL/6 mice at 6 hours after transient middle cerebral artery occlusion (MCAo; 60 minutes) to investigate the impact of MSCs on stroke-induced immunodepression. Transplantation of syngeneic splenocytes or phosphate-buffered saline (PBS) served as controls. An immune status was determined by flow cytometry on days 3 and 14 after MCAo, which did not reveal any negative effects of cell transplantation on stroke-induced immunodepression. Although our mMSCs were found to exert immunosuppressive effects in vitro, stroke-mediated immune cell dysfunction was not altered by mMSCs in ex-vivo stimulation assays with lipopolysaccharide or concanavalin A. Moreover, systemic inflammatory cytokine levels (interleukin-6, tumor necrosis factorα, interferonγ, monocyte chemoattractant protein-1) remained unchanged in the sera of mice after cerebral ischemia and cell transplantation. These results reduce safety concerns about MSC administration in ongoing clinical stroke trials.
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Project description:The role of bradykinin (BK) receptors in activating and sensitizing peripheral nociceptors is well known. Recently, we showed that spinal dynorphin was pronociceptive through direct or indirect BK receptor activation. Here, we explored the potential role of BK receptors in pain associated with persistent pancreatitis in rats.Experimental pancreatitis and abdominal hypersensitivity were induced by intravenous administrations of dibutyltin dichloride (DBTC). [des-Arg-Leu]BK (B1 antagonist) and HOE 140 (B2 antagonist) were given by intraperitoneal or intrathecal injection. Dynorphin antiserum was given intrathecally. Reverse transcription-polymerase chain reaction was used to detect spinal mRNA for BK receptors.Dibutyltin dichloride-induced pancreatitis upregulated B1 and B2 mRNA in the thoracic dorsal root ganglion and B2, but not B1, in the pancreas. No changes in spinal B1 or B2 mRNA were observed. Intraperitoneal or intrathecal administration of HOE 140 dose dependently abolished DBTC-induced abdominal hypersensitivity, whereas [des-Arg-Leu]BK was without effect by either route of administration. Antiserum to dynorphin (intrathecal) abolished DBTC-induced hypersensitivity.These results suggest that blockade of peripheral or spinal BK B2 receptors may be an effective approach for diminishing pain associated with pancreatitis. Moreover, it is suggested that spinal dynorphin may maintain pancreatitis pain through direct or indirect activation of BK B2 receptors in the spinal cord.
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Project description:Allogeneic hematopoietic stem cell transplantation (HSCT) is a technologically complicated procedure that represents the only cure for many hematologic malignancies. However, HSCT is often complicated by life-threatening toxicities related to the chemo-radiation conditioning regimen, poor engraftment of donor HSCs, the hyperinflammatory syndrome of graft-versus-host disease (GVHD), infection risks from immunosuppression, and end-organ damage. Bone marrow stromal cells (MSCs), also known as "mesenchymal stromal cells," not only play a nurturing role in the hematopoietic microenvironment but also can differentiate into other cell types of mesenchymal origin. MSCs are poorly immunogenic, and they can modulate immunological responses through interactions with a wide range of innate and adaptive immune cells to reduce inflammation. They are easily expanded ex vivo and after infusion, home to sites of injury and inflammation to promote tissue repair. Despite promising early trial results in HSCT with significant responses that have translated into survival benefits, there have been significant barriers to successful commercialization as an off-the-shelf therapy. Current efforts with MSCs in the HSCT setting are geared toward determining the factors determining potency, understanding the precise mechanisms of action in human HSCT, knowing their kinetics and fate, optimizing dose and schedule, incorporating biomarkers as response surrogates, addressing concerns about safety, optimizing clinical trial design, and negotiating the uncharted regulatory landscape for licensable cellular therapy.
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Project description:BackgroundThis study aims to evaluate the quality of preclinical data, determine the effect sizes, and identify experimental measures that inform efficacy using mesenchymal stromal (or stem) cells (MSC) therapy in animal models of rheumatoid arthritis (RA).MethodsLiterature searches were performed on MSC preclinical studies to treat RA. MSC treatment effect sizes were determined by the most commonly used outcome measures, including paw thickness, clinical score, and histological score.FindingsA total of 48 studies and 94 treatment arms were included, among which 42 studies and 79 treatment arms reported that MSC improved outcomes. The effect sizes of RA treatments using MSC, when compared to the controls, were: paw thickness was ameliorated by 53.6% (95% confidence interval (CI): 26.7% -80.4%), histological score was decreased by 44.9% (95% CI: 33.3% -56.6%), and clinical score was decreased by 29.9% (95% CI: 16.7% -43.0%). Specifically, our results indicated that human umbilical cord derived MSC led to large improvements of the clinical score (-42.1%) and histological score (-51.4%).InterpretationTo the best of our knowledge, this meta-analysis is to quantitatively answer whether MSC represent a robust RA treatment in animal models. It suggests that in preclinical studies, MSC have consistently exhibited therapeutic benefits. The findings demonstrate a need for considering variations in different animal models and treatment protocols in future studies using MSC to treat RA in humans to maximise the therapeutic gains in the era of precision medicine.FundsNIH [1DP2CA195763], Baylx Inc.: BI-206512, NINDS/NIH Training Grant [Award# NS082174].
| S-EPMC6796567 | biostudies-literature