Injection Of Stromal Cells Research Articles

Cell Therapy by Mesenchymal Stromal Cells Versus Myoblasts in a Pig Model of Urinary Incontinence.

The leading cause of stress urinary incontinence (SUI) in women is the urethral sphincter muscle deficiency caused by mechanical stress during pregnancy and vaginal delivery. In men, prostate cancer surgery and injury of local nerves and muscles are associated with incontinence. Current treatment often fails to satisfy the patient's needs. Cell therapy may improve the situation. We therefore investigated the regeneration potential of cells in ameliorating sphincter muscle deficiency and UI in a large animal model. Urethral sphincter deficiency was induced surgically in gilts by electrocautery and balloon dilatation. Adipose tissue-derived stromal cells (ADSCs) and myoblasts from Musculus semitendinosus were isolated from male littermates, expanded, characterized in depth for expression of marker genes and in vitro differentiation, and labeled. The cells were injected into the deficient sphincter complex of the incontinent female littermates. Incontinent gilts receiving no cell therapy served as controls. Sphincter deficiency and functional regeneration were recorded by monitoring the urethral wall pressure during follow-up by two independent methods. Cells injected were detected in vivo during follow-up by transurethral fluorimetry, ex vivo by fluorescence imaging, and in cryosections of tissues targeted by immunofluorescence and by polymerase chain reaction of the sex-determining region Y (SRY) gene. Partial spontaneous regeneration of sphincter muscle function was recorded in control gilts, but the sphincter function remained significantly below levels measured before induction of incontinence (67.03% ± 14.00%, n = 6, p < 0.05). Injection of myoblasts yielded an improved sphincter regeneration within 5 weeks of follow-up but did not reach significance compared to control gilts (81.54% ± 25.40%, n = 5). A significant and full recovery of the urethral sphincter function was observed upon injection of ADSCs within 5 weeks of follow-up (100.4% ± 23.13%, n = 6, p < 0.05). Injection of stromal cells provoked slightly stronger infiltration of CD45pos leukocytes compared to myoblasts injections and controls. The data of this exploratory study indicate that ADSCs inherit a significant potential to regenerate the function of the urethral sphincter muscle.

The ocular graft-versus-host disease: the path from current knowledge to future managements.

Graft-versus-host disease (GVHD) is one of the major complications of allogenic haematopoietic stem cell transplantation (HSCT). The manifestation of ocular GVHD (oGVHD) is variable and may involve cornea, lacrimal gland, conjunctiva, eyelid, and/or nasolacrimal duct. We reviewed and summarized the current managements of oGVHD with specific focus on the emerging therapeutic advances. PubMed, Web of Science, and Google Scholar were searched for relevant literatures published within 20 years. Keywords used included "Graft-Versus-Host Disease", "GVHD", "ocular", "ocular surface", "ocular GVHD", "oGVHD", "dry eye", "keratitis", etc. RESULTS: Current managements of oGVHD can be classified into topical immunosuppressants, local tear-preservatory treatments, local non-pharmacological/surgical interventions, and systemic treatments. Additionally, some innovative therapies with promising treatment effects have been proposed, including topical target therapies, epitheliotrophic and neurotrophic treatments, recombinant DNase eye drops, mesenchymal stromal cell injection, and more. Clinical managements of oGVHD are administered in a symptom-based, stepwise manner. The advances in innovative therapies may help improve clinical outcomes, and it is essential that physicians stay updated with these novel treatment options.

Dissemination of Multipotent Stromal Cells in the Organism after Their Injection into Intact and Resected Liver in the Experiment.

The possibility of dissemination of bone marrow multipotent stromal cells stained with Vybrant CM-Dil after injection into an intact and resected liver was studied using luminescence microscopy. Labeled cells were found in the kidneys, spleen, lungs, axillary, mesenteric, and inguinal lymph nodes. We observed dissemination of multipotent stromal cells and their detritus throughout the body that occurred only after filtration in the lungs, where most cells underwent destruction. Perivascularly located macrophages in various organs can phagocytize multipotent stromal cells and their detritus from blood vessels. The content of objects labeled with Vybrant CM-Dil in distant organs was significantly lower after multipotent stromal cell injection into the resected liver, which was associated with the deposition of cells in the damaged area of the organ and their partial entry into the abdominal cavity.

The 2020 NBA Orthobiologics Consensus Statement

This 2020 NBA Orthobiologics Consensus Statement provides a concise summary of available literature and practical clinical guidelines for team physicians and players. We recognize that orthobiologic injections are a generally safe treatment modality with a significant potential to reduce pain and expedite early return to play in specific musculoskeletal injuries. The use of orthobiologics in sports medicine to safely reduce time loss and reinjury is of considerable interest, especially as it relates to the potential effect on a professional athlete. While these novel substances have potential to enhance healing and regeneration of injured tissues, there is a lack of robust data to support their regular use at this time. There are no absolutes when considering the implementation of orthobiologics, and unbiased clinical judgment with an emphasis on player safety should always prevail. Current best evidence supports the following: Key Points There is support for the use of leukocyte-poor platelet-rich plasma in the treatment of knee osteoarthritis. There is support for consideration of using leukocyte-rich platelet-rich plasma for patellar tendinopathy. The efficacy of using mesenchymal stromal cell injections in the management of joint and soft tissue injuries remains unproven at this time. There are very few data to suggest that current cell therapy treatments lead to any true functional tissue regeneration. Meticulous and sterile preparation guidelines must be followed to minimize the risk for infection and adverse events if these treatments are pursued.Given the high variability in orthobiologic formulations, team physicians must stay up-to-date with the most recent peer-reviewed literature and orthobiologic preparation protocols for specific injuries.Evidence-based treatment algorithms are necessary to identify the optimal orthobiologic formulations for specific tissues and injuries in athletes.Changes in the regulatory environment and improved standardization are required given the exponential increase in utilization as novel techniques and substances are introduced into clinical practice.

Clinical trial evaluating the efficacy of systemic mesenchymal stromal cell injections for the treatment of severe and chronic radiotherapy-induced abdomino-pelvic complications refractory to standard therapy

Background & Aim The late adverse effects of pelvic radiotherapy concern 5 to 10% of patients, which could be life threatening. However, a clear medical consensus concerning the clinical management of such healthy tissue sequelae does not exist. Our group has demonstrated in preclinical animal models that systemic mesenchymal stromal stem cells (MSCs) injection is a promising approach for the medical management of gastrointestinal disorder after irradiation. Methods, Results & Conclusion In a phase 1 clinical trial, we have shown that the clinical status of four first patients suffering from severe pelvic side effects (Epinal accident) was improved following MSC injection (figure 1 and 2). Two patients revealed a substantiated clinical response for pain and hemorrhage after MSC therapy. The frequency of painful diarrhea diminished from 6/d to 3/d after the first and 2/d after the 2nd MSC injection in one patient. A beginning fistulization process could be stopped in one patient resulting in a stable remission for more than 3 years of follow-up. A modulation of the lymphocyte subsets towards a regulatory pattern and diminution of activated T cells accompanies the clinical response. MSC therapy was effective on pain, diarrhea, hemorrhage, inflammation, fibrosis and limited fistulization. No toxicity was observed (Table). We are now starting a clinical research protocol for patients with post-radiation abdominal and pelvic complications (figure 3) who have not seen their symptoms improve after conventional treatments (NCT02814864, Trial evaluating the efficacy of systemic MSC injections for the treatment of severe and chronic radiotherapy-induced abdomino-pelvic complications refractory to standard therapy (PRISME). It involves the participation of 6 radiotherapy services for the recruitment of 12 patients. They will all be treated and followed up in the hematology department of Saint Antoine Hospital. The cells will be prepared in two production centers (EFS Mondor and CTSA). Treatment is a suspension of allogeneic MSCs. Eligible patients must have a grade greater than 2 for rectoragy or hematuria at inclusion and absence of active cancer. Each patient receives 3 injections of MSCs at 7-day intervals. Patients will be followed up over a 12-month period. The main objective is a decrease of one grade on the LENT SOMA scale for rectorrhagia or hematuria. The secondary objective is to reduce the frequency of diarrhea; analgesic consumption, pain and improved quality of life.

The Effects of Facial Lipografting on Skin Quality: A Systematic Review.

Autologous lipografting for improvement of facial skin quality was first described by Coleman in 2006. The current dogma dictates that adipose tissue-derived stromal cells that reside in the stromal vascular fraction of lipograft contribute to skin rejuvenation (e.g., increased skin elasticity), a more homogenous skin color, and softening of skin texture. Nowadays, many studies have been reported on this "skin rejuvenation" effect of autologous fat grafting. This systematic review was undertaken to assess the efficacy of autologous lipografting on skin quality. The MEDLINE, Embase, Cochrane Central, Web of Science, and Google Scholar databases were searched for studies evaluating the effect of autologous lipografting on facial skin quality (May 11, 2018). Outcomes of interest were skin texture, color, and elasticity in addition to histologic outcomes and number of complications. Nine studies were included, with 301 patients treated in total. No meta-analysis could be performed because of heterogeneity of the metrics and outcomes. Eight studies reported increased skin elasticity; improvement in skin texture; and a more homogeneous skin color after treatment with lipografting, cellular stromal vascular fraction, or nanofat. One study reported no increased skin elasticity after lipografting. Histologic improvement was seen after lipografting and adipose tissue-derived stromal cell injections. However, in general, the level of evidence of the included studies was low. No serious complications were reported. Autologous facial lipografting and cellular stromal vascular fraction and adipose tissue-derived stromal cell injections hardly seem to improve facial skin quality but can be considered a safe procedure.

Adipose Stromal Cells Injection in the Myocardium for Induction of Revascularization

Adipose Stromal Cells Injection in the Myocardium for Induction of Revascularization

Возможность развития воспалительных повреждений интактной печени после инъекции мультипотентных стромальных клеток в эксперименте

Возможность развития воспалительных повреждений интактной печени после инъекции мультипотентных стромальных клеток в эксперименте

Correction to: Possibility of Aggravation of Tissue Sclerosis after Injection of Multipotent Mesenchymal Stromal Cells Near the Forming Cicatrix in the Experiment.

The author name G. A. Chastikina should read G. A. Chastikin.

Possibility of Aggravation of Tissue Sclerosis after Injection of Multipotent Mesenchymal Stromal Cells Near the Forming Cicatrix in the Experiment.

The peculiarities of tissue sclerosis after injection of autologous bone marrow multipotent mesenchymal stromal cells transfected with GFP gene and stained with Vybrant CM-Dil cell membrane dye were studied by light microscopy with luminescence. The surgical intervention consisting in ligation of the great vein was followed by tissue sclerotic transformation caused by direct damage and chronic inflammation caused by the presence of slowly resorbed ligature. Injection of stromal cells after this intervention led to formation of more extensive scar. This can attest to the possibility of stromal cells differentiation into connective tissue cells, fibroblasts, and stimulation of proliferation and collagen synthesis by host fibroblasts. A decrease in the volume of dense fibrous connective tissue due to scar reorganization at latter terms cannot not excluded.

Mesenchymal stromal cell injection promotes vocal fold scar repair without long-term engraftment

BackgroundRegenerative medicine holds promise for restoring voice in patients with vocal fold scarring. As experimental treatments approach clinical translation, several considerations remain. Our objective was to evaluate efficacy and biocompatibility of four bone marrow mesenchymal stromal cell (BM-MSC) and tunable hyaluronic acid based hydrogel (HyStem-VF) treatments for vocal fold scar using clinically acceptable materials, a preclinical sample size and a dosing comparison. MethodsVocal folds of 84 rabbits were injured and injected with four treatment variations (BM-MSC, HyStem-VF, and BM-MSC in HyStem-VF at two concentrations) 6 weeks later. Efficacy was assessed with rheometry, real-time polymerase chain reaction (RT-PCR) and histology at 2, 4 and 10 weeks following treatment. Lung, liver, kidney, spleen and vocal folds were screened for biocompatibility by a pathologist. Results and discussionPersistent inflammation was identified in all hydrogel-injected groups. The BM-MSC alone treatment appeared to be the most efficacious and safe, providing an early resolution of viscoelasticity, gene expression consistent with desirable extracellular matrix remodeling (less fibronectin, collagen 1α2, collagen 3, procollagen, transforming growth factor [TGF]β1, alpha smooth muscle actin, interleukin-1β, interleukin-17β and tumor necrosis factor [TNF] than injured controls) and minimal inflammation. Human beta actin expression in BM-MSC–treated vocal folds was minimal after 2 weeks, suggesting that paracrine signaling from the BM-MSCs may have facilitated tissue repair.

Morphological Changes in Rat Uterine Tissues and Possibility of Spontaneous Labor as a Result of Injection of Multipotent Mesenchymal Stromal Cells against the Background of Hydrometra.

The possibility of pregnancy and labor was evaluated and tissue changes after injection of autologous bone marrow multipotent mesenchymal stromal cells with transfected GFP gene were studied in rats with experimental hydrometra. Injection of stromal cells to the uterine cicatrix increased the number of vessels (vascular walls or their elements) formed de novo with participation of injected cells. The animals produced progeny 2 estrous cycles earlier, the percentage of "puerperal" rats in this group was higher, their progeny was more numerous and they had the maximum numbers of little rats. The maternal mortality was lower after injection of stromal cells. Injection of stromal cells led to development of a trend to more rapid reparative processes in the uterus in animals with cicatricial stenosis of its lumen.

The effect of low intensity pulsed ultrasound treatment combined with mesenchymal stromal cell injection for cartilage regeneration in a knee osteochondral defect model of rats.

The effect of low intensity pulsed ultrasound treatment combined with mesenchymal stromal cell injection for cartilage regeneration in a knee osteochondral defect model of rats.

Mesenchymal stromal cell injection protects against oxidative stress in Escherichia coli–induced acute lung injury in mice

Background aimsStem cells may be a promising therapy for acute respiratory distress syndrome. Recent in vivo and in vitro studies suggested that the mesenchymal stromal cells (MSCs) have anti-oxidative stress properties. We hypothesized that intravenous injection of bone marrow–derived mesenchymal stem cells (MSCs) could attenuate Escherichia coli–induced acute lung injury (ALI) in mice by controlling the oxidative stress status. MethodsEighty mice were randomly divided into four groups: group 1 (control group) received 25 μL of saline as a vehicle; group 2 contained E coli–induced ALI mice; group 3 included mice that received MSCs before induction of ALI; group 4 included mice that received MSCs after induction of ALI. Lung samples were isolated and assayed for oxidative stress variables and histopathologic analysis. Total anti-oxidant capacity was measured in broncho-alveolar lavage. ResultsPre- and post-injury MSC injection increased survival, reduced pulmonary edema and attenuated lung injuries in ALI mice. Histologically, MSCs exhibited a considerable degree of preservation of the pulmonary alveolar architecture. An increase of anti-oxidant enzyme activities and a decrease of myeloperoxidase activity and malondialdehyde levels in the MSC recipient groups versus the ALI group were found. Furthermore, the total anti-oxidant capacity and reduced glutathione levels were significantly increased in MSCs recipient groups versus the ALI group. Weak +ve inducible nitric oxide synthase immuno-expression in groups that received MSCs was detected. Pre-injury MSC injection showed better effects than did post-injury MSC injection. ConclusionsSystemic bone marrow–derived MSC injection was effective in modulating the oxidative stress status in E coli–induced acute lung injury in mice.

Intravenous and Intratracheal Mesenchymal Stromal Cell Injection in a Mouse Model of Pulmonary Emphysema

The aim of this study was to characterize the evolution of lung function and -structure in elastase-induced emphysema in adult mice and the effect of mesenchymal stromal cell (MSC) administration on these parameters. Adult mice were treated with intratracheal (4.8 units/100 g bodyweight) elastase to induce emphysema. MSCs were administered intratracheally or intravenously, before or after elastase injection. Lung function measurements, histological and morphometric analysis of lung tissue were performed at 3 weeks, 5 and 10 months after elastase and at 19, 20 and 21 days following MSC administration. Elastase-treated mice showed increased dynamic compliance and total lung capacity, and reduced tissue-specific elastance and forced expiratory flows at 3 weeks after elastase, which persisted during 10 months follow-up. Histology showed heterogeneous alveolar destruction which also persisted during long-term follow-up. Jugular vein injection of MSCs before elastase inhibited deterioration of lung function but had no effects on histology. Intratracheal MSC treatment did not modify lung function or histology. In conclusion, elastase-treated mice displayed persistent characteristics of pulmonary emphysema. Jugular vein injection of MSCs prior to elastase reduced deterioration of lung function. Intratracheal MSC treatment had no effect on lung function or histology.

Effect of intrastriatal mesenchymal stromal cell injection on progression of a murine model of Krabbe disease

One of a family of devastating lysosomal storage disorders, Krabbe disease is characterized by demyelination, psychosine accumulation, and inflammation. Affected infants rarely survive longer than 2 years. Using the twitcher mouse model of the disease, this study evaluated the potential of intrastriatal injection of adipose or bone marrow-derived mesenchymal stromal cells (MSCs) as a treatment option. Neonatal pups were injected with MSCs at 3–4 days of age and subjected to a battery of behavioral tests beginning at 15 days. While MSC injection failed to increase lifespan of twitchers, improvements in rotarod performance and twitching severity were observed at 27–38 days of age using MSCs derived from bone marrow. This study tested several different tasks developed in adult mice for evaluation of disease progression in immature twitchers. Rotarod was both reliable and extremely sensitive. Automated gait analysis using the Treadscan program was also useful for early evaluation of differences prior to overt gait dysfunction. Finally, this study represents the first use of the Stone T-maze in immature mice. Validation of rotarod and automated gait analysis for detection of subtle differences in disease progression is important for early stage efforts to develop treatments for juvenile disorders.

Delayed Administration of Human Umbilical Tissue-Derived Cells Improved Neurological Functional Recovery in a Rodent Model of Focal Ischemia

The short time window required by neuroprotective strategies for successful treatment of patients with ischemic stroke precludes treatment for most. However, clinical therapies based on neuroregeneration might extend this therapeutic time window and thus address a significant unmet need. Human umbilical tissue-derived cells have shown great potential as neuroregenerative candidates for stroke treatment. The effectiveness of intravenous administration of human umbilical tissue-derived cells was tested in a rodent middle cerebral artery stroke model in a dose escalation study (doses tested: 3×10(5), 1×10(6), 3×x10(6), or 1×10(7) cells/injection) followed by a time-of-administration study (time after stroke: Day 1, Day 7, Day 30, and Day 90 at a dose of 5×10(6) cells/injection). Controls were phosphate-buffered saline injections and human bone marrow-derived mesenchymal stromal cell injections. Post-treatment outcome tools included the modified neurological severity score and the adhesive removal tests. Histology was performed on all cases to evaluate synaptogenesis, neurogenesis, angiogenesis, and cell apoptosis. Statistically significant improvements of human umbilical tissue-derived cell treatment versus phosphate-buffered saline in modified neurological severity scores and adhesive test results were observed for doses≥3×10(6) cells up to 30 days poststroke. At doses≥3×10(6), histological evaluations confirmed enhanced synaptogenesis, vessel density, and reduced apoptosis in the ischemic boundary zone and increased proliferation of progenitor cells in the subventricular zone of human umbilical tissue-derived cell-treated animals versus phosphate-buffered saline controls. These results indicate effectiveness of intravenous administration of human umbilical tissue-derived cells in a rodent stroke model compared with phosphate-buffered saline control and warrant further investigation for possible use in humans.

Cell Therapy in a Mouse Model of Immune-Mediated Bone Marrow Failure.

Immune-mediated bone marrow (BM) failure has been modeled in the mouse by infusion of lymph node cells from allogeneic C57BL/6 (B6) donors into major or minor histocompatibility antigen-mismatched recipients (Chen et al., Blood 2004; Bloom et al., Exp Hematol 2004, Chen et al., J Immunol 2007). Co-infusion of limited numbers of CD4+CD25+ regulatory T lymphocytes (Tregs) can alleviate clinical manifestations by suppressing the expansion of pathogenic T cells (Chen et al., J Immunol 2007). In the current study, we investigated the effectiveness of Tregs and suppressor cells contained in BM stroma in this fatal disease. Infusion of fewer than 3 × 103 Tregs to each recipient mouse had only a minor effect in preserving BM cells and did not prevent pancytopenia. Fifteen-50 × 103 thymic Tregs was moderately protective: blood WBC, RBC, platelet and BM cell counts at three weeks after cell infusion were 197%, 116%, 155% and 158% of those of control animals that did not receive Treg infusion; 5–10 × 103 B6 splenic Tregs produced the largest effect as WBC, RBC, platelet and BM cell counts were 275%, 143%, 276%, and 198% of controls. Overall, Treg therapy was helpful but its effectiveness was limited and variable among individual recipients as no antigen-specific Tregs can be identified for the treatment of BM failure. Learned about the immunosuppressive effects of mesenchymal stem cells (MSCs), we went on to test the effectiveness of stromal cells as another therapeutic modality for BM failure, since stromal cells contain MSCs. These cells were derived from B6 BM by culture in α-modified Eagle medium at 33°C with 5% CO2 for two weeks. After separating the non-adherent cells, we detached the adherent stromal cells and infused them into TBI + B6 LN-infused C.B10 mice. Injection of 106 stromal cells at the time of LN cell infusion effectively preserved WBCs (3.09 ± 0.51 vs 0.61 ± 0.18), RBCs (8.72 ± 0.14 vs 3.52 ± 0.46), platelets (924 ± 93 vs 147 ± 25) and BM cells (186.6 ± 8.7 vs 52.7 ± 7.8) when compared to LN-cell-infused mice without stromal cell addition. Delayed stromal cell injection at day 9 after LN cell infusion had only a mild effect on the preservation of RBCs (147%), platelets (276%) and BM cells (223%) and no effect on WBCs (64%), and infusion of non-adherent cells from the same stromal cell culture had no therapeutic effect. Stromal cell-infused mice had higher proportion of FoxP3+CD4+ cells in the peripheral blood (59.7 ± 10.7% vs 29.8 ± 5.4%) and more Lin−CD117+CD34− hematopoietic stem and progenitor cells in the BM (591 ± 95 vs 60 ± 43, thousand) in comparison to LN cell infused mice without stromal cell treatment. Mitigation of pathogenic T cells, including both CD4 and CD8 T lymphocytes, is the potential mechanism for the effectiveness of Treg and stromal cell therapies that helped to protect hematopoietic stem and progenitor cells in the BM of affected animals. [Display omitted]

Bone Marrow Stromal Cells Injection into Heart using the Newly Developed Catheter for Transendocardial Cell Transplantation

Purpose: Recently, cell transplantation is focused on as the useful method to treat severe cardiovascular disease. There are several ways to inject cell to target lesion including transendocardial method, but the useful tools to inject cells still need to be explored. In this study, we examined the efficacy and feasibility of the newly developed catheter for transendocardial delivery, injecting bone marrow stromal cell (BMSC) in porcine infarcted heart.

Simultaneous Injection of Bone Marrow Cells and Stromal Cells into Bone Marrow Accelerates Hematopoiesis In Vivo

We have previously demonstrated that stromal cells can support the proliferation and differentiation of hematopoietic cells in vitro and in vivo and that a major histocompatibility complex restriction exists between hematopoietic stem cells and stromal cells. We have also found that intra-bone marrow (IBM) injection of allogeneic bone marrow cells (BMCs) leads to more rapid reconstitution of hematopoietic cells than intravenous injection. In the present study, we examine the effect of simultaneous injection of stromal cells and BMCs into the same bone marrow on the recovery of donor hematopoietic cells and demonstrate that simultaneous IBM injection of BMCs plus stromal cells is more effective in reconstituting recipients with donor hematopoietic cells than intravenous injection of BMCs plus stromal cells or IBM injection of BMCs alone.