Delivery Of Mesenchymal Stem Cells Research Articles

Use of human bone marrow mesenchymal stem cells immortalized by the expression of telomerase in wound healing in diabetic rats.

Diabetes mellitus is associated with neural and micro- and macrovascular complications. Therapeutic options for these complications are limited and the delivery of mesenchymal stem cells into lesions have been reported to improve the healing process. In this work, the effects of the administration of a lineage of human bone marrow mesenchymal stem cells immortalized by the expression of telomerase (hBMSC-TERT) as a potential therapeutic tool for wound healing in diabetic rats were investigated. This is the first description of the use of these cells in diabetic wounds. Dorsal cutaneous lesions were made in streptozotocin-induced diabetic rats and hBMSC-TERT were subcutaneously administered around the lesions. The healing process was evaluated macroscopically, histologically, and by birefringence analysis. Diabetic wounded rats infused with hBMSC-TERT (DM-TERT group) and the non-diabetic wounded rats not infused with hBMSC-TERT (CW group) had very similar patterns of fibroblastic response and collagen proliferation indicating improvement of wound healing. The result obtained by birefringence analysis was in accordance with that obtained by the histological analysis. The results indicated that local administration of hBMSC-TERT in diabetic wounds improved the wound healing process and may become a therapeutic option for wounds in individuals with diabetes.

Alzheimer's disease neuropathology is exacerbated following traumatic brain injury. Neuroprotection by co-administration of nanowired mesenchymal stem cells and cerebrolysin with monoclonal antibodies to amyloid beta peptide.

Military personnel are prone to traumatic brain injury (TBI) that is one of the risk factors in developing Alzheimer's disease (AD) at a later stage. TBI induces breakdown of the blood-brain barrier (BBB) to serum proteins into the brain and leads to extravasation of plasma amyloid beta peptide (ΑβP) into the brain fluid compartments causing AD brain pathology. Thus, there is a need to expand our knowledge on the role of TBI in AD. In addition, exploration of the novel roles of nanomedicine in AD and TBI for neuroprotection is the need of the hour. Since stem cells and neurotrophic factors play important roles in TBI and in AD, it is likely that nanodelivery of these agents exert superior neuroprotection in TBI induced exacerbation of AD brain pathology. In this review, these aspects are examined in details based on our own investigations in the light of current scientific literature in the field. Our observations show that TBI exacerbates AD brain pathology and TiO2 nanowired delivery of mesenchymal stem cells together with cerebrolysin-a balanced composition of several neurotrophic factors and active peptide fragments, and monoclonal antibodies to amyloid beta protein thwarted the development of neuropathology following TBI in AD, not reported earlier.

Magnet-targeted delivery of bone marrow-derived mesenchymal stem cells improves therapeutic efficacy following hypoxic-ischemic brain injury.

Stem cell transplantation may represent a feasible therapeutic option for the recovery of neurological function in children with hypoxic-ischemic brain injury; however, the therapeutic efficacy of bone marrow-derived mesenchymal stem cells largely depends on the number of cells that are successfully transferred to the target. Magnet-targeted drug delivery systems can use a specific magnetic field to attract the drug to the target site, increasing the drug concentration. In this study, we found that the double-labeling using superparamagnetic iron oxide nanoparticle and poly-L-lysine (SPIO-PLL) of bone marrow-derived mesenchymal stem cells had no effect on cell survival but decreased cell proliferation 48 hours after labeling. Rat models of hypoxic-ischemic brain injury were established by ligating the left common carotid artery. One day after modeling, intraventricular and caudal vein injections of 1 × 105 SPIO-PLL-labeled bone marrow-derived mesenchymal stem cells were performed. Twenty-four hours after the intraventricular injection, magnets were fixed to the left side of the rats' heads for 2 hours. Intravoxel incoherent motion magnetic resonance imaging revealed that the perfusion fraction and the diffusion coefficient of rat brain tissue were significantly increased in rats treated with SPIO-PLL-labeled cells through intraventricular injection combined with magnetic guidance, compared with those treated with SPIO-PLL-labeled cells through intraventricular or tail vein injections without magnetic guidance. Hematoxylin-eosin and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining revealed that in rats treated with SPIO-PLL-labeled cells through intraventricular injection under magnetic guidance, cerebral edema was alleviated, and apoptosis was decreased. These findings suggest that targeted magnetic guidance can be used to improve the therapeutic efficacy of bone marrow-derived mesenchymal stem cell transplantation for hypoxic-ischemic brain injury. This study was approved by the Animal Care and Use Committee of The Second Hospital of Dalian Medical University, China (approval No. 2016-060) on March 2, 2016.

Comparison of quantitative and qualitative scoring approaches for radiation-induced pulmonary fibrosis as applied to a preliminary investigation into the efficacy of mesenchymal stem cell delivery methods in a rat model.

Objectives:Compare a quantitative, algorithm-driven, and qualitative, pathologist-driven, scoring of radiation-induced pulmonary fibrosis (RIPF). And using these scoring models to derive preliminary comparisons on the effects of different mesenchymal stem cell (MSC) administration modalities in reducing RIPF.Methods25 rats were randomized into 5 groups: non-irradiated control (CG), irradiated control (CR), intraperitoneally administered granulocyte-macrophage colony stimulating factor or GM-CSF (Drug), intravascularly administered MSC (IV), and intratracheally administered MSC (IT). All groups, except CG, received an 18 Gy conformal dose to the right lung. Drug, IV and IT groups were treated immediately after irradiation. After 24 weeks of observation, rats were euthanized, their lungs excised, fixed and stained with Masson’s Trichrome. Samples were anonymized and RIPF was scored qualitatively by a certified pathologist and quantitatively using ImageScope. An analysis of association was conducted, and two binary classifiers trained to validate the integrity of both qualitative and quantitative scoring. Differences between the treatment groups, as assessed by the pathologist score, were then tested by variance component analysis and mixed models for differences in RIPF outcomes.Results:There is agreement between qualitative and quantitative scoring for RIPF grades from 4 to 7. Both classifiers performed similarly on the testing set (AUC = 0.923) indicating accordance between the qualitative and quantitative scoring. For comparisons between MSC infusion modalities, the Drug group had better outcomes (mean pathologist scoring of 3.96), correlating with significantly better RIPF outcomes than IV [lower by 0.97, p = 0.047, 95% CI = (0.013, 1.918)] and resulting in an improvement over CR [lower by 0.93, p = 0.037, 95% CI = (0.062, 1.800].Conclusion:Quantitative image analysis may help in the assessment of therapeutic interventions for RIPF and can serve as a scoring surrogate in differentiating between severe and mild cases of RIPF. Preliminary data demonstrate that the use of GM-CSF was best correlated with lower RIPF severity.Advances in knowledgeQuantitative image analysis can be a viable supplemental system of quality control and triaging in situations where pathologist work hours or resources are limited. The use of different MSC administration methods can result in different degrees of MSC efficacy and study outcomes.

An MSC bone-homing compound, Rab001, increases bone mass and reduces the incidence of osteonecrosis in a glucocorticoid-induced osteonecrosis mouse model.

Currently, there are no effective medications to either prevent or slow the progression of atraumatic osteonecrosis (ON).The objective of this study is to determine the effects of bone-targeted delivery of mesenchymal stem cells on the prevalence of ON in a glucocorticoid (GC)-induced mouse model. Eight-week-old male BALB/c mice were randomized into groups that received placebo (PL), prednisolone (GC), or concurrent treatments with GC+mesenchymal stromal cells (MSCs), Rab001 or GC+Rab001 + MSCs. Human parathyroid hormone (hPTH) was used as a positive control for bone anabolism. Mice were killed after 30days, and quantitative measurements of bone mass, bone strength, prevalent ON at the distal femoral epiphysis (DFE) were performed. Angiogenesis was accessed by RNA-Seq, the circulating angiogenic markers, as well as by immunohistochemical staining. We have showed that a novel agent, Rab001 that can noncovalently bind to mesenchymal stem cells (MSC) and direct them to the bone, prevents the incidence of glucocorticoid-induced osteonecrosis in the mouse. In contrast, PTH, a bone anabolic treatment, preserves bone mass but sustains higher ON incidence than Rab001+/- MSC-treated mice. The results of these experiments reveal that glucocorticoids increase the prevalence of ON, and agents that prevent loss of bone vascularity appear to prevent the development of ON. This intervention might be useful in patients with early stages of atraumatic ON.

Mesenchymal Stem Cells as Therapeutic Agents and Novel Carriers for the Delivery of Candidate Genes in Acute Kidney Injury.

Acute kidney injury (AKI) is a heterogeneous syndrome characterized by a dramatic increase in serum creatinine. Mild AKI may merely be confined to kidney damage and resolve within days; however, severe AKI commonly involves extrarenal organ dysfunction and is associated with high mortality. There is no specific pharmaceutical treatment currently available that can reverse the course of this disease. Notably, mesenchymal stem cells (MSCs) show great promise for the management of AKI by targeting multiple pathophysiological pathways to facilitate tubular epithelial cell repair. It has been well established that the unique characteristics of MSCs make them ideal vectors for gene therapy. Thus, genetic modification has been attempted to achieve improved therapeutic outcomes in the management of AKI by overexpressing trophic cytokines or facilitating MSC delivery to renal tissues. The present article provides a comprehensive review of genetic modification strategies targeted at optimizing the therapeutic potential of MSCs in AKI.

Human decellularized adipose matrix derived hydrogel assists mesenchymal stem cells delivery and accelerates chronic wound healing.

Biological scaffolds based stem cell delivery methods have emerged as a promising approach for tissue repair and regeneration. Here we developed a hydrogel biological scaffold from human decellularized adipose matrix (hDAM) for human adipose-derived stem cells (hASCs) delivery to accelerate chronic wound healing. The hDAM hydrogel was prepared by pepsin mediated digestion and pH controlled neutralization. The morphology, survival, proliferation, and angiogenic paracrine activity of hASCs cultured in the hydrogel were assessed. Moreover, the therapeutic efficacy of the hASCs-hydrogel composite for impaired wound healing was evaluated by using a full-thickness wound model on diabetic mouse. The developed hDAM hydrogel was a thermosensitive hydrogel, presented the biochemical complexity of native extracellular matrix and formed a porous nanofiber structure after gelation. The hydrogel can support hASCs adhesion, survival, and proliferation. Compared to standard culture condition, hASCs cultured in the hydrogel exhibited enhanced paracrine activity with increased secretion of hepatocyte growth factor. In the diabetic mice model with excisional full-thickness skin wounds, mice treated with the hASCs-hydrogel composite displayed accelerated wound closure and increased neovascularization. Our results suggested that the developed hDAM hydrogel can provide a favorable microenvironment for hASCs with augmented regeneration potential to accelerate chronic wound healing.

Combinatorial intranasal delivery of bone marrow mesenchymal stem cells and insulin-like growth factor-1 improves neurovascularization and functional outcomes following focal cerebral ischemia in mice

Bone marrow mesenchymal stem cell (BMSC) transplantation is a promising treatment for ischemic stroke that carries a severe mortality and disability burden amongst the adult population globally. Thus far, BMSC transplantation has been insufficient for ameliorating neurological deficits resulting from cerebral ischemia. This shortcoming may be an outcome due to poor homing and viability of grafted cells in ischemic brain that limit the potential therapeutic benefits of BMSC transplantation. Insulin-like growth factor-1 (IGF-1), a potent anti-apoptotic agent, exerts neuroprotective effects in ischemic stroke as well as rescuing neuronal death in vitro. We hypothesized that IGF-1 could also protect BMSCs from apoptotic death, and examined whether the combination of BMSCs with IGF-1 can enhance functional recovery outcomes in mice following cerebral ischemia. Intranasal administration of BMSCs with IGF-1 was applied in a mouse focal ischemic stroke model. Our in vitro results indicated that BMSCs treated with IGF-1 exhibited less apoptotic death induced by oxygen-glucose deprivation (OGD), and an improved migratory capacity. At 14 days after ischemic insult, the combination of BMSCs with IGF-1 resulted in a larger number of NeuN/BrdU and Glut-1/BrdU co-labeled cells in the areas contiguous to the ischemic core than IGF-1 or BMSC treatment alone. Western blot assays demonstrated that the protein levels of BDNF, VEGF and Ang-1 were significantly upregulated in the peri-infarct region in the combination treatment group compared with single IGF- 1 or BMSC treatment. Co-administration of BMSCs and IGF-1 markedly increases local cerebral blood flow and promoted better functional behavior outcomes. These data suggest that intranasal delivery of BMSCs in conjunction with IGF-1 strengthened functional recovery following ischemia via increasing neurogenesis and angiogenesis, providing a novel optimized strategy for improving the therapeutic efficacy of BMSC transplantation for ischemia.

Balancing biological and biomechanical performance in intervertebral disc repair: a systematic review of injectable cell delivery biomaterials.

Discogenic back pain is a common condition without approved intervertebral disc (IVD) repair therapies. Cell delivery using injectable biomaterial carriers offers promise to restore disc height and biomechanical function, while providing a functional niche for delivered cells to repair degenerated tissues. This systematic review advances the injectable IVD cell delivery biomaterials field by characterising its current state and identifying themes of promising strategies. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to screen the literature and 183 manuscripts met the inclusion criteria. Cellular and biomaterial inputs, and biological and biomechanical outcomes were extracted from each study. Most identified studies targeted nucleus pulposus (NP) repair. No consensus exists on cell type or biomaterial carrier, yet most common strategies used mesenchymal stem cell (MSC) delivery with interpenetrating network/co-polymeric (IPN/CoP) biomaterials composed of natural biomaterials. All studies reported biological outcomes with about half the studies reporting biomechanical outcomes. Since the IVD is a load-bearing tissue, studies reporting compressive and shear moduli were analysed and two major themes were found. First, a competitive balance, or ‘seesaw’ effect, between biomechanical and biological performance was observed. Formulations with higher moduli had inferior cellular performance, and vice versa. Second, several low-modulus biomaterials had favourable biological performance and matured throughout culture duration with enhanced extracellular matrix synthesis and biomechanical moduli. Findings identify an opportunity to develop next-generation biomaterials that provide high initial biomechanical competence to stabilise and repair damaged IVDs with a capacity to promote cell function for long-term healing.

Abstract 16757: Immunomodulatory Hydrogel Promotes Survival of Mesenchymal Stem Cells in a Rat Model of Myocardial Infarction

Introduction: Stem cell (SC) therapy is a potential method of repairing the heart after injury. However, SCs have been shown to have poor survival after transplantation, at least in part, due to a hostile pro-inflammatory ischemic myocardium. Thus, there is significant interest in the identification of strategies that can increase the retention/survival of SCs after transplantation. Here we seek to investigate whether the use of an immunomodulatory hydrogel, containing anti-inflammatory sinapic acid (SA), promotes the survival of SCs after transplantation. Methods: Myocardial infarction was induced in rats followed by the delayed delivery of A) mesenchymal stem cells (MSCs), B) MSCs in a hydrogel without SA or C) MSCs in a hydrogel containing SA (10μM). Delivery of MSCs (7.5 x 10 5 in 30μL) occurred 7 days after MI, representing the subacute stage and to minimize acute inflammation. Survival of MSCs, stably expressing firefly luciferase under the constitutive CMV promoter, was followed longitudinally using bioluminescence imaging. Results: Panels A-C provide representative images of the viability of MSCs in different groups, with the quantification shown in panel D. There were no differences in survival when MSCs were delivered alone (A) or in a hydrogel without SA (B). However, the survival of MSCs was significantly increased when they were transplanted in a hydrogel with the anti-inflammatory SA (C). Conclusions: Here we provide evidence of the potential for an immunomodulatory hydrogel to enhance the viability of MSCs after infarction, which may lead to improvement of cardiac function. Furthermore, use of this hydrogel in combination with stem cells could be a potential therapeutic strategy for ameliorating cardiac repair after significant damage.

Abstract 359: Systemic Administration of Allogeneic Mesenchymal Stem Cells Attenuates Post-Resuscitation Left Ventricular Dysfunction in a Porcine Model of Cardiac Arrest

Introduction: Advances in CPR have increased the likelihood of achieving ROSC after cardiac arrest (CA), but >50% of initially resuscitated patients die before hospital discharge. Evidence that a systemic inflammatory response exacerbates post-ROSC injury supports investigation of anti-inflammatory therapies in this setting. Accordingly, we tested the efficacy of allogeneic mesenchymal stem cell (MSC) administration early after ROSC in a porcine model of CA. Methods: Swine (n=33) were subjected to 10 min CA followed by mechanical CPR with defibrillation and intravenous epinephrine (EPI; 0.015 mg/kg). Animals that achieved ROSC (n=19) were blindly randomized to intraventricular saline (n=9) or allogeneic bone marrow-derived MSCs (55±2 x 10 6 ; n=10) 30 min post-ROSC. Intravenous EPI was given during the post-ROSC period as needed to maintain MAP ≥60 mmHg. Left ventricular (LV) function and plasma cardiac troponin I (cTnI) were assessed for 4 hr post-ROSC, at which time heart tissue was collected to assess myocardial inflammation (RT-PCR). Results: Compared with saline-treated controls, MSC-treated animals exhibited improved post-ROSC LV wall thickening ( A ) and lower cTnI levels, indicative of reduced myocardial injury. By design, both groups had a similar post-ROSC MAP and cardiac output, but the saline group required significantly more EPI ( B ). Although a similar degree of monocyte infiltration (CCR2) and macrophage expansion (CD68) was observed in both groups, MSCs increased expression of the anti-inflammatory marker Arginase1 ( C ) and tended to attenuate the post-ROSC rise in circulating IL-6 ( D ). Conclusion: Early post-ROSC delivery of allogeneic MSCs attenuates LV dysfunction and reduces the need for pharmacologic hemodynamic support after CA in swine. These results indicate that systemic MSC administration may be an effective immunomodulatory strategy to reduce post-resuscitation injury, particularly if protective effects extend to the brain.

An injectable and antibacterial calcium phosphate scaffold inhibiting Staphylococcus aureus and supporting stem cells for bone regeneration

Staphylococcus aureus (S. aureus) is the major pathogen for osteomyelitis, which can lead to bone necrosis and destruction. There has been no report on antibacterial calcium phosphate cement (CPC) against S. aureus. The aims of this study were to: (1) develop novel antibacterial CPC-chitosan-alginate microbead scaffold; (2) investigate mechanical and antibacterial properties of CPC-chitosan-penicillin-alginate scaffold; (3) evaluate the encapsulation and delivery of human umbilical cord mesenchymal stem cells (hUCMSCs). Flexural strength, elastic modulus and work-of-fracture of the CPC-chitosan-penicillin-alginate microbeads scaffold and CPC-chitosan scaffold were evaluated. Penicillin release profile and antibacterial effects on S. aureus were determined. The hUCMSC delivery and release from penicillin-alginate microbeads were investigated. Injectable CPC-chitosan-penicillin-alginate microbeads scaffold was developed for the first time. CPC-chitosan-penicillin-alginate microbeads scaffold had a flexural strength of 3.16 ± 0.55 MPa, matching that of cancellous bone. With sustained penicillin release, the new scaffold had strong antibacterial effects on S. aureus, with an inhibition zone diameter of 32.2 ± 2.5 mm, greater than that of penicillin disk control (15.1 ± 2.0 mm) (p < 0.05). Furthermore, this injectable and antibacterial scaffold had no toxic effects, yielding excellent hUCMSC viability, which was similar to that of CPC control without antibacterial activity (p > 0.05). CPC-chitosan-penicillin-microbeads scaffold had injectability, good strength, strong antibacterial effects, and good biocompatibility to support stem cell viability for osteogenesis. CPC-chitosan-penicillin-microbeads scaffold is promising for dental, craniofacial and orthopedic applications to combat infections and promote bone regeneration.

Engineered Cell Sheets for the Effective Delivery of Adipose-Derived Stem Cells for Tendon-to-Bone Healing

Background: Efforts are being made to treat rotator cuff tears (RCTs) that exhibit poor healing and high retear rates. Tendon-to-bone healing using mesenchymal stem cells is being explored, but research is needed to establish effective delivery options. Purpose: To evaluate the effects of an adipose-derived stem cell (ADSC) sheet on mesenchymal stem cell delivery for tendon-to-bone healing of a chronic RCT in rats and to demonstrate that ADSC sheets enhance tendon-to-bone healing. Study Design: Controlled laboratory study. Methods: Mesenchymal stem cells were obtained from rat adipose tissue, and a cell sheet was prepared using a temperature-responsive dish. To evaluate the efficacy of stem cells produced in a sheet for the lesion, the experiment was conducted with 3 groups: repair group, cell sheet transplantation after repair group, and cell sheet–only group. Histological, biomechanical, and micro–computed tomography (micro-CT) results were compared among the groups. Results: Hematoxylin and eosin staining for histomorphological analysis revealed that the cell sheet transplantation after repair group (5.75 ± 0.95) showed statistically significant higher scores than the repair (2.75 ± 0.50) and cell sheet–only (3.25 ± 0.50) groups (P < .001). On safranin O staining, the cell sheet transplantation after repair group (0.51 ± 0.04 mm2) had a larger fibrocartilage area than the repair (0.31 ± 0.06 mm2) and cell sheet–only (0.32 ± 0.03 mm2) groups (P = .001). On micro-CT, bone volume/total volume values were significantly higher in the cell sheet transplantation after repair group (23.98% ± 1.75%) than in the other groups (P < .039); there was no significant difference in the other values. On the biomechanical test, the cell sheet transplantation after repair group (4 weeks after repair) showed significantly higher results than the other groups (P < .005). Conclusion: Our study shows that engineered stem cells are a clinically feasible stem cell delivery tool for rotator cuff repair. Clinical Relevance: This laboratory study provides evidence that ADSCs are effective in repairing RCTs, which are common sports injuries.

Intranasal mesenchymal stem cell therapy to boost myelination after encephalopathy of prematurity.

Encephalopathy of prematurity (EoP) is a common cause of long‐term neurodevelopmental morbidity in extreme preterm infants. Diffuse white matter injury (dWMI) is currently the most commonly observed form of EoP. Impaired maturation of oligodendrocytes (OLs) is the main underlying pathophysiological mechanism. No therapies are currently available to combat dWMI. Intranasal application of mesenchymal stem cells (MSCs) is a promising therapeutic option to boost neuroregeneration after injury. Here, we developed a double‐hit dWMI mouse model and investigated the therapeutic potential of intranasal MSC therapy. Postnatal systemic inflammation and hypoxia‐ischemia led to transient deficits in cortical myelination and OL maturation, functional deficits and neuroinflammation. Intranasal MSCs migrated dispersedly into the injured brain and potently improved myelination and functional outcome, dampened cerebral inflammationand rescued OL maturation after dWMI. Cocultures of MSCs with primary microglia or OLs show that MSCs secrete factors that directly promote OL maturation and dampen neuroinflammation. We show that MSCs adapt their secretome after ex vivo exposure to dWMI milieu and identified several factors including IGF1, EGF, LIF, and IL11 that potently boost OL maturation. Additionally, we showed that MSC‐treated dWMI brains express different levels of these beneficial secreted factors. In conclusion, the combination of postnatal systemic inflammation and hypoxia‐ischemia leads to a pattern of developmental brain abnormalities that mimics the clinical situation. Intranasal delivery of MSCs, that secrete several beneficial factors in situ, is a promising strategy to restore myelination after dWMI and subsequently improve the neurodevelopmental outcome of extreme preterm infants in the future.

Simultaneous impact of atorvastatin and mesenchymal stem cells for glioblastoma multiform suppression in rat glioblastoma multiform model

Glioblastoma multiform (GBM) is known as an aggressive glial neoplasm. Recently incorporation of mesenchymal stem cells with anti-tumor drugs have been used due to lack of immunological responses and their easy accessibility. In this study, we have investigated the anti-proliferative and apoptotic activity of atorvastatin (Ator) in combination of mesenchymal stem cells (MSCs) on GBM cells in vitro and in vivo. The MSCs isolated from rats and characterized for their multi-potency features. The anti-proliferative and migration inhibition of Ator and MSCs were evaluated by MTT and scratch migration assays. The annexin/PI percentage and cell cycle arrest of treated C6 cells were evaluated until 72 h incubation. The animal model was established via injection of C6 cells in the brain of rats and subsequent injection of Ator each 3 days and single injection of MSCs until 12 days. The growth rate, migrational phenotype and cell cycle progression of C6 cells decreased and inhibited by the interplay of different factors in the presence of Ator and MSCs. The effect of Ator and MSCs on animal models displayed a significant reduction in tumor size and weight. Furthermore, histopathology evaluation proved low hypercellularity and mitosis index as well as mild invasive tumor cells for perivascular cuffing without pseudopalisading necrosis and small delicate vessels in Ator + MSCs condition. In summary, Ator and MSCs delivery to GBM model provides an effective strategy for targeted therapy of brain tumor.

A barrier against reactive oxygen species: chitosan/acellular dermal matrix scaffold enhances stem cell retention and improves cutaneous wound healing

BackgroundStem cell therapies have gained great attention for providing novel solutions for treatment of various injuries and diseases due to stem cells’ self-renewal, ability to differentiate into various cell types, and favorite paracrine function. Nevertheless, the low retention of transplanted stem cell still limits their clinical applications such as in wound healing in view of an induced harsh microenvironment rich in reactive oxygen species (ROS) during inflammatory reactions.MethodsHerein, a novel chitosan/acellular dermal matrix (CHS/ADM) stem cell delivery system is developed, which is of great ROS scavenging activity and significantly attenuates inflammatory response.ResultUnder ROS microenvironment, this stem cell delivery system acts as a barrier, effectively scavenging an amount of ROS and protecting mesenchymal stem cells (MSCs) from the oxidative stress. It notably regulates intracellular ROS level in MSCs and reduces ROS-induced cellular death. Most importantly, such MSCs delivery system significantly enhances in vivo transplanted stem cell retention, promotes the vessel growth, and accelerates wound healing.ConclusionsThis novel delivery system, which overcomes the limitations of conventional plain collagen-based delivery system in lacking of ROS-environmental responsive mechanisms, demonstrates a great potential use in stem cell therapies in wound healing.

Delayed Intramyocardial Delivery of Stem Cells after Ischemia Reperfusion Injury in a Murine Model.

There is significant interest in the use of stem cells (SCs) for the recovery of cardiac function in individuals with myocardial injuries. Most commonly, cardiac stem cell therapy is studied by delivering SCs concurrently with the induction of myocardial injury. However, this approach presents two significant limitations: the early hostile pro-inflammatory ischemic environment may affect the survival of transplanted SCs, and it does not represent the subacute infarction scenario where SCs will likely be used. Here we describe a two-part series of surgical procedures for the induction of ischemia-reperfusion injury and delivery of mesenchymal stem cells (MSCs). This method of stem cell administration may allow for the longer viability and retention around damaged tissue by circumventing the initial immune response. A model of ischemia reperfusion injury was induced in mice accompanied by the delivery of mesenchymal stem cells (3.0 x 105), stably expressing the reporter gene firefly luciferase under the constitutively expressed CMV promoter, intramyocardially 7 days later. The animals were imaged via ultrasound and bioluminescent imaging for confirmation of injury and injection of cells, respectively. Importantly, there was no added complication rate when performing this two-procedure approach for SC delivery. This method of stem cell administration, collectively with the utilization of state-of-the-art reporter genes, may allow for the in vivo study of viability and retention of transplanted SCs in a situation of chronic ischemia commonly seen clinically, while also circumventing the initial pro-inflammatory response. In summary, we established a protocol for the delayed delivery of stem cells into the myocardium, which can be used as a potential new approach in promoting regeneration of the damaged tissue.

Strategies in Organ Preservation-A New Golden Age.

Strategies in Organ Preservation-A New Golden Age.

Immediate Intracoronary Delivery of Human Umbilical Cord Mesenchymal Stem Cells Reduces Myocardial Injury by Regulating the Inflammatory Process Through Cell-Cell Contact with T Lymphocytes.

Inflammatory response regulation is a mechanism through which human umbilical cord mesenchymal stem cells (HUCMSCs) improve myocardial ischemia reperfusion injury (IRI); however, the timing of HUCMSC delivery to achieve maximum effectiveness is controversial. To investigate the effects of HUCMSC delivery on the acute inflammatory stage of IRI, we transplanted HUCMSCs or HUCMSCs with cyclosporin A (CsA) through the coronary artery simultaneously during ischemia reperfusion in pigs. Ferumoxytol-labeled HUCMSCs (HUCMSC), HUCMSCs with cyclosporin A (HUCMSC+CsA), and PBS (control) groups were investigated to evaluate the homing of transplanted cells and changes in infarct features, cardiac activity, and inflammatory response at three time points post-transplantation. Animals were sacrificed 2 weeks later for histological analysis of the hearts. We detected Prussian blue-dyed granules distributed around T lymphocyte clusters in the infarct area in the HUCMSC group. Infarct size and collagen deposition in the infarct area were lower in the HUCMSC group than in the control and HUCMSC+CsA groups. Cardiac function was mildly impaired in both the control and HUCMSC groups, whereas added CsA had a more severe impact. The levels of proinflammatory markers were lower in the HUCMSC group than in the control group at 24-h follow-up, and the difference was more significant after adding CsA. There were more CD3+ T lymphocytes and Foxp3+ Tregs in the HUCMSC group infarct area than in the other two groups. Proliferation rate of T lymphocytes was higher in the HUCMSC group than in the other two groups. Indirect co-culture experiments in vitro showed that MSCs promoted the generation of CD4+CD25+ Foxp3+Tregs through a paracrine mechanism. These results indicate that immediate intracoronary delivery of HUCMSCs after ischemia reperfusion can reduce acute myocardial IRI and promote myocardial repair, mainly through T lymphocyte interactions to regulate the intense inflammatory response during the acute inflammatory stage.

Intravenous delivery of mesenchymal stem cells protects both white and gray matter in spinal cord ischemia

Ischemic spinal cord injury (iSCI) is a devastating complication of aortic surgery, with few strategies for prevention. Intravenous infusion of mesenchymal stem cells (MSCs) for iSCI has been shown to provide functional improvement through protection of gray matter. The purpose of this study was to investigate additional mechanisms which may exert therapeutic efficacy in iSCI.Severe iSCI was created to occlude the descending aorta, which was cross-clamped 5 mm distal to the left subclavian artery for 16 min. One day after iSCI induction, iSCI rats were randomized into two groups: one received intravenous infusion of MSCs (MSC-group), the other received vehicle (no cells; vehicle-group). Locomotor function and in vivo MRI were recorded. H&E, Nissl and toluidine blue stainings, immunohistochemical analysis, diffusion tensor imaging (DTI), and the assessment of blood-spinal cord barrier (BSCB) stability were performed.MSC treated animals exhibited gradual improvement in hind-limb locomotor function during the 4-week study period; however the vehicle-treated group displayed persistent motor deficits. In the MSC-treated group we observed the protection of white and gray matter volume reduction of axonal and neuronal loss or degeneration and preservation of microvasculature including BSCB function.Intravenous infusion of MSCs may provide therapeutic efficacy to improve functional outcomes in a rat model of severe iSCI via protection of white and gray matter.