Benefits Of Mesenchymal Stem Cells Research Articles

Benefits of mesenchymal stem cells after partial bladder outlet obstruction

Partial bladder outlet obstruction (pBOO) results in significant morbidity and mortality in the pediatric and adult populations. Mesenchymal stem cells (MSC) have been widely studied in many organ systems for the treatment and prevention of fibrotic and inflammatory conditions. Therefore, we hypothesize that systemic administration of MSC will demonstrate short-term biochemical, histological, and urodynamic benefits in an animal model for pBOO. After University ethics approval, 5 × 106 green fluorescent protein GFP-labeled MSC were intravenously injected concurrently with pBOO in adult Sprague-Dawley rats. Five groups (n=3/group) were analyzed: a) unobstructed controls; b) pBOO for seven days with intravenous MSC (7d+MSC); c) pBOO for seven days without intravenous MSC (7d-MSC); d) pBOO for 14 days with intravenous MSC (14d+MSC), e) pBOO for 14 days without MSC (14d-MSC). Urodynamics were performed at the end of the experimental period and bladders were weighed. Immunohistochemistry was performed for GFP detection and reverse transcription polymerase chain reaction (RT-PCR) to detect mRNA of: TGF-B, HIF-1a, RhoA, GRP-78, lumican, and decorin. All animals remained healthy. GFP was detected in all treatment groups. MSC treatment resulted in a significant decrease in bladder capacity (0.91 cc vs. 2.15 cc, p=0.04). Treatment also resulted in significant decreases in mRNA levels of: TGF-B, HIF-1a, Rho-A, and GRP-78. Systemic treatment with MSC was well tolerated and resulted in MSC accumulation after pBOO. Despite our low numbers, we were able to successfully demonstrate short-term urodynamic improvements and widespread, significant decreases in inflammatory mediators. We believe that this decreased inflammatory cascade will help prevent long-term detrusor deterioration.

Neuroprotective Potential of Mesenchymal Stem Cell-Based Therapy in Acute Stages of TNBS-Induced Colitis in Guinea-Pigs.

Background & AimsThe therapeutic benefits of mesenchymal stem cells (MSCs), such as homing ability, multipotent differentiation capacity and secretion of soluble bioactive factors which exert neuroprotective, anti-inflammatory and immunomodulatory properties, have been attributed to attenuation of autoimmune, inflammatory and neurodegenerative disorders. In this study, we aimed to determine the earliest time point at which locally administered MSC-based therapies avert enteric neuronal loss and damage associated with intestinal inflammation in the guinea-pig model of colitis.MethodsAt 3 hours after induction of colitis by 2,4,6-trinitrobenzene-sulfonate (TNBS), guinea-pigs received either human bone marrow-derived MSCs, conditioned medium (CM), or unconditioned medium by enema into the colon. Colon tissues were collected 6, 24 and 72 hours after administration of TNBS. Effects on body weight, gross morphological damage, immune cell infiltration and myenteric neurons were evaluated. RT-PCR, flow cytometry and antibody array kit were used to identify neurotrophic and neuroprotective factors released by MSCs.ResultsMSC and CM treatments prevented body weight loss, reduced infiltration of leukocytes into the colon wall and the myenteric plexus, facilitated repair of damaged tissue and nerve fibers, averted myenteric neuronal loss, as well as changes in neuronal subpopulations. The neuroprotective effects of MSC and CM treatments were observed as early as 24 hours after induction of inflammation even though the inflammatory reaction at the level of the myenteric ganglia had not completely subsided. Substantial number of neurotrophic and neuroprotective factors released by MSCs was identified in their secretome.ConclusionMSC-based therapies applied at the acute stages of TNBS-induced colitis start exerting their neuroprotective effects towards enteric neurons by 24 hours post treatment. The neuroprotective efficacy of MSC-based therapies can be exerted independently to their anti-inflammatory effects.

Infusion of mesenchymal stem cells protects lung transplants from cold ischemia-reperfusion injury in mice.

Cold ischemia-reperfusion injury (IRI) is a major cause of graft failure in lung transplantation. Despite therapeutic benefits of mesenchymal stem cells (MSCs) in attenuating acute lung injury, their protection of lung transplants from cold IRI remains elusive. The present study was to test the efficacy of MSCs in the prevention of cold IRI using a novel murine model of orthotopic lung transplantation. Donor lungs from C57BL/6 mice were exposed to 6 h of cold ischemia before transplanted to syngeneic recipients. MSCs were isolated from the bone marrows of C57BL/6 mice for recipient treatment. Gas exchange was determined by the measurement of blood oxygenation, and lung injury and inflammation were assessed by histological analyses. Intravenously delivered MSC migration/trafficking to the lung grafts occurred within 4-hours post-transplantation. As compared to untreated controls, the graft arterial blood oxygenation (PaO2/FiO2) capacity was significantly improved in MSC-treated recipients as early as 4 h post-reperfusion and such improvement continued over time. By 72 h, oxygenation reached normal level that was not seen in controls. MSCs treatment conferred significant protection of the grafts from cold IRI and cell apoptosis, which is correlated with less cellular infiltration, a decrease in proinflammatory cytokines (TNF-α, IL-6) and toll-like receptor 4, and an increase in anti-inflammatory TSG-6 generation. MSCs provide significant protection against cold IRI in lung transplants, and thus may be a promising strategy to improve outcomes after lung transplantation.

Mesenchymal Stem Cell Therapy Stimulates Endogenous Host Progenitor Cells to Improve Colonic Epithelial Regeneration

Patients who undergo pelvic radiotherapy may develop severe and chronic complications resulting from gastrointestinal alterations. The lack of curative treatment highlights the importance of novel and effective therapeutic strategies. We thus tested the therapeutic benefit of mesenchymal stem cells (MSC) treatment and proposed molecular mechanisms of action. MSC efficacy was tested in an experimental model of radiation-induced severe colonic ulceration histologically similar to that observed in patients. In this model, MSC from bone marrow were administered intravenously, immediately or three weeks (established lesions) after irradiation. MSC therapy reduces radiation-induced colonic ulceration and increases animal survival. MSC treatment induces therapeutic efficacy whatever the time of cell infusion. Infused-MSC engraft in the colon but also increase endogenous MSC mobilization in blood that have lasting benefits over time. In vitro analysis demonstrates that the MSC effect is mediated by paracrine mechanisms through the non-canonical WNT (Wingless integration site) pathway. In irradiated rat colons, MSC treatment increases the expression of the non-canonical WNT4 ligand by epithelial cells. The epithelial regenerative process is improved after MSC injection by stimulation of colonic epithelial cells positive for SOX9 (SRY-box containing gene 9) progenitor/stem cell markers. This study demonstrates that MSC treatment induces stimulation of endogenous host progenitor cells to improve the regenerative process and constitutes an initial approach to arguing in favor of the use of MSC to limit/reduce colorectal damage induced by radiation.

Cell interactions between human progenitor-derived endothelial cells and human mesenchymal stem cells in a three-dimensional macroporous polysaccharide-based scaffold promote osteogenesis

Several studies have reported the benefits of mesenchymal stem cells (MSCs) for bone tissue engineering. However, vascularization remains one of the main obstacles that must be overcome to reconstruct large bone defects. In vitro prevascularization of the three-dimensional (3-D) constructs using co-cultures of human progenitor-derived endothelial cells (PDECs) with human bone marrow mesenchymal stem cells (HBMSCs) appeared as a potential strategy. However, the crosstalk between the two lineages has been studied in two-dimensional (2-D), but remains unknown in 3-D. The aim of this study is to investigate the cell interactions between PDECs and HBMSCs in a porous matrix composed of polysaccharides. This biodegradable scaffold promotes cell interactions by inducing multicellular aggregates composed of HBMSCs surrounded by PDECs. Cell aggregation contributes to the formation of junctional proteins composed of Connexin43 (Cx43) and VE-cadherin, and an activation of osteoblastic differentiation of HBMSCs stimulated by the presence of PDECs. Inhibition of Cx43 by mimetic peptide 43GAP27 induced a decrease in mRNA levels of Cx43 and all the bone-specific markers. Finally, subcutaneous implantations for 3 and 8weeks in NOG mice revealed an increase in osteoid formation with the tissue-engineered constructs seeded with HBMSCs/PDECs compared with those loaded with HBMSCs alone. Taking together, these results demonstrate that this 3-D microenvironment favored cell communication, osteogenesis and bone formation.

Abstract 3671: Intra-Carotid Mesenchymal Stem Cell Therapy is Superior to Intravenous delivery in Rat Model of Cerebral Ischemia

INTRODUCTION: There are multiple pre-clinical studies showing significant neurological functional benefit of Mesenchymal Stem Cells (MSCs) in cerebral ischemia. MSCs are adult bone marrow derived cells that have a high potential for clinical translation. The optimal route of MSC delivery has not been established. Intra-carotid (IC) delivery via catheters has several attributes attractive for clinical application & may be superior to intravenous (IV) delivery as it circumvents systemic trapping of cells and allows more cells to reach the target lesion. In our previous study using the rat rMCAo model, we found the maximum tolerated dose (MTD) of IC MSCs to be 1 x 10^5 HYPOTHESIS: We tested the hypothesis that the MTD of IC mesenchymal stem cells (MSCs) is more efficacious as compared to IV MSCs and IC control. We further hypothesized that the MTD of IC MSCs given at 24 hours is more efficacious as compared to IC MSCs at 60 minutes. METHODS: 34 female Sprague-Dawley rats underwent 90 minutes reversible middle cerebral artery occlusion (rMCAo). At 60 minutes or 24 hours post rMCAo, rats were assigned to receive: allogeneic IC MSCs at a dose of 1x 10^5 or IC phosphate buffered saline (PBS) 0.5ml or allogeneic intravenous (IV) MSCs 1 x 10^6 & rMCAo with no treatment (sham). Primary outcome measures were blinded neurodeficit score and infarct volume at 4 weeks. RESULTS: At 24 hours post rMCAo, there was no significant difference in the neurodeficit score (NDS) amongst the groups. At four weeks post treatment, the IC MSC group showed a significantly lower NDS (7%_3.3) as compared to IV MSCs (10.2%_1.5, p=0.042); In subgroup analysis, IC MSCs given at 60 minutes showed no significant difference compared to other groups, but IC MSC given at 24 hours showed a significantly lower neurodeficit score (5.8 %_2.6) as compared to IC PBS (10.8%_1.2, p=0.003), IV MSCs (10.2 %_1.5, p=0.005) and Sham (10%_ 3.4, p=0.018) ( Fig1 .). The mean infarct volume of the group treated with IC MSCs was significantly lower as compared to IC PBS (18cc%_ 8 vs. 50cc%_17, p=0.043). On infarct topography frequency map comparison, we found a significantly decreased volume of infarction in the cortical regions in IC MSC group as compared to IC PBS group. CONCLUSIONS: Treatment with maximum tolerated IC MSC dose of 1 x 10^5 post rMCAO results in superior functional outcome when compared with IV MSC 1 x 10^6, IC PBS and sham rats. Additionally, IC MSC at 24 hours is more efficacious than IC MSC at 60 minutes. There is also a significant decrease in infarct volume in IC MSC treated rats when compared with IC PBS. The IC MSCs may ameliorate injury in the cortex surrounding the core.

Human Umbilical Cord Blood-Derived Mesenchymal Stem Cell Therapy Promotes Functional Recovery of Contused Rat Spinal Cord through Enhancement of Endogenous Cell Proliferation and Oligogenesis

Numerous studies have shown the benefits of mesenchymal stem cells (MSCs) on the repair of spinal cord injury (SCI) model and on behavioral improvement, but the underlying mechanisms remain unclear. In this study, to investigate possible mechanisms by which MSCs contribute to the alleviation of neurologic deficits, we examined the potential effect of human umbilical cord blood-derived MSCs (hUCB-MSCs) on the endogenous cell proliferation and oligogenesis after SCI. SCI was injured by contusion using a weight-drop impactor and hUCB-MSCs were transplanted into the boundary zone of the injured site. Animals received a daily injection of bromodeoxyuridine (BrdU) for 7 days after treatment to identity newly synthesized cells of ependymal and periependymal cells that immunohistochemically resembled stem/progenitor cells was evident. Behavior analysis revealed that locomotor functions of hUCB-MSCs group were restored significantly and the cavity volume was smaller in the MSCs-transplanted rats compared to the control group. In MSCs-transplanted group, TUNEL-positive cells were decreased and BrdU-positive cells were significantly increased rats compared with control group. In addition, more of BrdU-positive cells expressed neural stem/progenitor cell nestin and oligo-lineage cell such as NG2, CNPase, MBP and glial fibrillary acidic protein typical of astrocytes in the MSC-transplanted rats. Thus, endogenous cell proliferation and oligogenesis contribute to MSC-promoted functional recovery following SCI.