• Allied disorders of Hirschsprung disease
• Chronic idiopathic intestinal pseudo-obstruction
• Hirschsprung disease
• Hypoganglionosis
• Regenerative therapy
• Stem cell therapy

• Hirschsprung Disease/therapy
• Hirschsprung Disease/surgery
• Humans
• Enteric Nervous System
• Regenerative Medicine/methods
• Intestinal Pseudo-Obstruction/therapy
• Embryonic Stem Cells/transplantation
• Stem Cell Transplantation/methods
• Induced Pluripotent Stem Cells/transplantation
• Intestine, Small
• Regeneration
• Muscle, Smooth
• Mesenchymal Stem Cell Transplantation/methods
• Abnormalities, Multiple/therapy
• Urinary Bladder/abnormalities
• Colon/abnormalities

• hip dysplasia
• mesenchymal stem cells
• platelet-rich plasma
• regenerative medicine

• aging
• companion animals
• mesenchymal stem cells
• regenerative medicine
• stem cell therapy
• veterinary use

• N/A Biopep

• Axonotmesis
• Conditioned media
• Mesenchymal stem cells
• Peripheral nerve injury
• Rabbit
• Sciatic nerve

• Canine
• clinical trials as topic
• feline
• regenerative medicines
• stem cells

Transplantation medicine is used for the treatment of severe canine diseases, and the dog leukocyte antigen (DLA) is considered to be important in graft rejection. However, the utility of direct sequencing of both DLA classes I and II has not been assessed thoroughly. Eight healthy beagles with identified DLA genes were divided into two sets of four dogs, each including one donor and three recipients for skin transplantation. The following recipients were selected: one dog with a complete match, one with a haploidentical match, and one with a complete mismatch of the DLA gene with the donor. Full-thickness skin segments were obtained from each donor and transplanted to the recipients. A mixed lymphocyte reaction (MLR) assay was performed and analyzed by flow cytometry. Skin grafts of DLA haploidentical and mismatched pairs were grossly rejected within 14 days, whereas in fully matched DLA pairs, survival was as long as 21 days. Histopathological evaluation also showed moderate to severe lymphocytic infiltration and necrosis in DLA mismatched pairs. As seen in the MLR assay, the stimulation index of DLA mismatched pairs was significantly higher than that of fully matched DLA pairs in both sets (P<0.001). The allogeneic transplantation results suggested that it is possible to prolong transplant engraftment by completely matching the DLA genotype between the donor and recipient. Additionally, the MLR assay may be used as a simplified in vitro method to select donors.

• cell therapy
• dog
• major histocompatibility complex
• skin graft

Limb wounds on horses are often slow to heal and are prone to developing exuberant granulation tissue (EGT) and close primarily through epithelialization, which results in a cosmetically inferior and non-durable repair. In contrast, wounds on the body heal rapidly and primarily through contraction and rarely develop EGT. Intravenous (IV) multipotent mesenchymal stromal cells (MSCs) are promising. They home and engraft to cutaneous wounds and promote healing in laboratory animals, but this has not been demonstrated in horses. Furthermore, the clinical safety of administering >1.00 × 10⁸ allogeneic MSCs IV to a horse has not been determined. A proof-of-principle pilot project was performed with two horses that were administered 1.02 × 10⁸ fluorescently labeled allogeneic cord blood-derived MSCs (CB-MSCs) following wound creation on the forelimb and thorax. Wounds and contralateral non-wounded skin were sequentially biopsied on days 0, 1, 2, 7, 14, and 33 and evaluated with confocal microscopy to determine presence of homing and engraftment. Results confirmed preferential homing and engraftment to wounds with persistence of CB-MSCs at 33 days following wound creation, without clinically adverse reactions to the infusion. The absence of overt adverse reactions allows further studies to determine effects of IV CB-MSCs on equine wound healing.

• equine limb wound
• exuberant granulation tissue
• horse
• intravenous
• stem cells

Articular cartilage damage and osteoarthritis (OA) are common orthopedic diseases in both humans and dogs. Once damaged, the articular cartilage seldom undergoes spontaneous repair because of its avascular, aneural, and alymphatic state, and the damage progresses to a chronic and painful situation. Dogs have distinctive characteristics compared to other laboratory animal species in that they share an OA pathology with humans. Dogs can also require treatment for naturally developed OA; therefore, effective treatment methods for OA are desired in veterinary medicine as well as in human medicine. Recently, interest has grown in regenerative medicine that includes the use of mesenchymal stem cells (MSCs). In cartilage repair, MSCs are a promising therapeutic tool due to their self-renewal capacity, ability to differentiate into cartilage, potential for trophic factor production, and capacity for immunomodulation. The MSCs from dogs (canine MSCs; cMSCs) share various characteristics with MSCs from other animal species, but they show some deviations, particularly in their differentiation ability and surface epitope expression. In vivo studies of cMSCs have demonstrated that intraarticular cMSC injection into cartilage lesions results in excellent hyaline cartilage regeneration. In clinical situations, cMSCs have shown great therapeutic effects, including amelioration of pain and lameness in dogs suffering from OA. However, some issues remain, such as a lack of regulations or guidelines and a need for unified methods for the use of cMSCs. This review summarizes what is known about cMSCs, including their in vitro characteristics, their therapeutic effects in cartilage lesion treatment in preclinical in vivo studies, their clinical efficacy for treatment of naturally developed OA in dogs, and the current limitations of cMSC studies.

• Mesenchymal stem cell
• Dog
• Cartilage
• Osteoarthritis
• Regenerative medicine
• Veterinary medicine

• dogs
• endothelial progenitor cells
• physiological assessment
• stem cells
• transplantation

• characterization
• clinical applications
• dog
• mesenchymal stem cells
• musculoskeletal
• soft tissue

• adipose stem cells
• angiogenic factors
• anti-inflammatory factor
• dogs
• transplantation

Mesenchymal stem cells (MSCs) have potent immunomodulatory functions and are a promising therapy for immune‐mediated inflammatory disorders. We previously demonstrated the efficacy of fresh, autologous, adipose‐derived MSCs (ASCs) to treat feline chronic gingivostomatitis (FCGS), a chronic oral mucosal inflammatory disease similar to human oral lichen planus. Here, we investigate the use of fresh allogeneic ASCs for treatment of FCGS in seven cats. Radiolabeled ASCs were also tracked systemically. Each cat received two intravenous injections of 20 million ASCs, 1 month apart. Oral inflammation, blood lymphocyte subsets, anti‐fetal bovine serum antibody levels, ASC crossmatching and serum proteins and cytokine concentrations were determined. Four of the 7 cats (57%) responded to treatment [complete clinical remission (n = 2) or substantial clinical improvement (n = 2)]. Three cats were nonresponders. Prior to therapy, most cats had increased circulating CD8+ T cells, decreased CD8^lo cells, and a decreased CD4/CD8 ratio, however clinical resolution was not associated with normalization of these parameters. Nonresponders showed more severe systemic inflammation (neutrophilia, hyperglobulinemia and increased interferon gamma and tumor necrosis factor alpha concentration) prior to ASC therapy. Clinical remission took up to 20 months and no clinical relapse has occurred. A higher fraction of radiolabeled ASCs were identified in the oral cavity of FCGS affected cats than the control cat. The administration of fresh, allogenic ASCs appeared to have lower clinical efficacy with a delayed response as compared to the fresh, autologous ASCs. In addition, the mechanism(s) of action for autologous and allogenic ASCs may differ in this model of oral inflammation. Stem Cells Translational Medicine2017;6:1710–1722

• Adipose-derived stem cells
• Allogeneic
• Cats
• Fresh
• Gingivostomatitis
• Immunomodulation
• Oral Mucosa

Mesenchymal stem cells have the ability to differentiate into various cell types, and thus have emerged as promising alternatives to chondrocytes in cell-based cartilage repair methods. The aim of this experimental study was to investigate the effect of bone marrow derived mesenchymal stem cells combined with platelet rich fibrin on osteochondral defect repair and articular cartilage regeneration in a canine model.

Osteochondral defects were created on the medial femoral condyles of 12 adult male mixed breed dogs. They were either treated with stem cells seeded on platelet rich fibrin or left empty. Macroscopic and histological evaluation of the repair tissue was conducted after four, 16 and 24 weeks using the International Cartilage Repair Society macroscopic and the O’Driscoll histological grading systems. Results were reported as mean and standard deviation (sd) and compared at different time points between the two groups using the Mann-Whitney U test, with a value < 0.05 considered statistically significant.

Higher cumulative macroscopic and histological scores were observed in stem cell treated defects throughout the study period with significant differences noted at four and 24 weeks (9.25, sd 0.5 vs 7.25, sd 0.95, and 10, sd 0.81 vs 7.5, sd 0.57; p < 0.05) and 16 weeks (16.5, sd 4.04 vs 11, sd 1.15; p < 0.05), respectively. Superior gross and histological characteristics were also observed in stem cell treated defects.

The use of autologous culture expanded bone marrow derived mesenchymal stem cells on platelet rich fibrin is a novel method for articular cartilage regeneration. It is postulated that platelet rich fibrin creates a suitable environment for proliferation and differentiation of stem cells by releasing endogenous growth factors resulting in creation of a hyaline-like reparative tissue.

Cite this article: D. Kazemi, K. Shams Asenjan, N. Dehdilani, H. Parsa. Canine articular cartilage regeneration using mesenchymal stem cells seeded on platelet rich fibrin: Macroscopic and histological assessments. Bone Joint Res 2017;6:98–107. DOI: 10.1302/2046-3758.62.BJR-2016-0188.R1.

• Articular cartilage
• Mesenchymal stem cells
• Platelet rich fibrin

• Acute Kidney Injury/chemically induced
• Acute Kidney Injury/therapy
• Animals
• Bone Marrow Cells/physiology
• Cisplatin/toxicity
• Dogs
• Glomerular Filtration Rate
• Kidney/physiopathology
• Mesenchymal Stem Cell Transplantation/veterinary
• Mesenchymal Stem Cells
• Regeneration/physiology
• Tumor Necrosis Factor-alpha

The past decade has witnessed an outstanding scientific production focused towards the possible clinical applications of mesenchymal stromal cells (MSCs) in autoimmune and chronic inflammatory diseases. This raised the need of novel standards to adequately address quality, efficacy and safety issues of this advanced therapy. The development of a streamlined regulation is currently hampered by the complexity of analyzing dynamic biological entities rather than chemicals. Although numerous pieces of evidence show efficacy in reducing intestinal inflammation, some inconsistencies between the mechanisms of action of rodent vs human MSCs suggest caution before assigning translational value to preclinical studies. Preliminary evidence from clinical trials showed efficacy of MSCs in the treatment of fistulizing Crohn’s disease (CD), and preparations of heterologous MSCs for CD treatment are currently tested in ongoing clinical trials. However, safety issues, especially in long-term treatment, still require solid clinical data. In this regard, standardized guidelines for appropriate dosing and methods of infusion could enhance the likelihood to predict more accurately the number of responders and the duration of remission periods. In addition, elucidating MSC mechanisms of action could lead to novel and more reliable formulations such as those derived from the MSCs themselves (e.g., supernatants).

• Mesenchymal stromal cells
• Mesenchymal stem cells
• Inflammatory bowel diseases
• Intestinal disorders
• Translational medicine

• Animals
• Biomarkers/metabolism
• Gastroenterology/legislation & jurisprudence
• Gastroenterology/methods
• Gastrointestinal Diseases/diagnosis
• Gastrointestinal Diseases/metabolism
• Gastrointestinal Diseases/physiopathology
• Gastrointestinal Diseases/surgery
• Government Regulation
• Health Policy
• Humans
• Mesenchymal Stem Cell Transplantation/adverse effects
• Mesenchymal Stem Cell Transplantation/legislation & jurisprudence
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/physiology
• Patient Safety
• Phenotype
• Regeneration
• Regenerative Medicine/legislation & jurisprudence
• Regenerative Medicine/methods
• Risk Factors
• Translational Research, Biomedical/legislation & jurisprudence
• Translational Research, Biomedical/methods
• Treatment Outcome

Treatment and repair of neurodegenerative diseases such as brain tumors, spinal cord injuries, and functional disorders, including Alzheimer’s disease, are challenging problems. A common treatment approach for such disorders involves the use of mesenchymal stem cells (MSCs) as an alternative cell source to replace injured cells. However, use of these cells in hosts may potentially cause adverse outcomes such as tumorigenesis and uncontrolled differentiation. In attempt to generate mesenchymal derived neural cells, we have infected MSCs with recombinant lentiviruses that expressed nerve growth factor (NGF) and assessed their neural lineage genes.

In this experimental study, we cloned the NGF gene sequence into a helper dependent lentiviral vector that contained the green fluorescent protein (GFP) gene. The recombinant vector was amplified in DH5 bacterial cells. Recombinant viruses were generated in the human embryonic kidney 293 (HEK-293) packaging cell line with the helper vectors and analyzed under fluorescent microscopy. Bone marrow mesenchymal cells were infected by recombinant viruses for three days followed by assessment of neural differentiation. We evaluated expression of NGF through measurement of the NGF protein in culture medium by ELISA; neural specific genes were quantified by real-time polymerase chain reaction (PCR).

We observed neural morphological changes after three days. Quantitative PCR showed that expressions of NESTIN, glial derived neurotrophic factor (GDNF), glial fibrillary acidic protein (GFAP) and Microtubule-associated protein 2 (MAP2) genes increased following induction of NGF overexpression, whereas expressions of endogenous NGF and brain derived neural growth factor (BDNF) genes reduced.

Ectopic expression of NGF can induce neurogenesis in MSCs. Direct injection of MSCs may cause tumorigenesis and an undesirable outcome. Therefore an alternative choice to overcome this obstacle may be the utilization of differentiated neural stem cells.

• ELISA
• Human Nerve Growth Factor
• Mesenchymal Stem Cells
• Neural Differentiation

• Adipose-derived stem cells
• Autologous
• Cats
• Fresh
• Gingivostomatitis
• Immunomodulation
• Oral mucosa

• Animals
• Autografts
• Cat Diseases/immunology
• Cat Diseases/pathology
• Cat Diseases/therapy
• Cats
• Female
• Humans
• Male
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/immunology
• Mesenchymal Stem Cells/pathology
• Stomatitis/immunology
• Stomatitis/pathology
• Stomatitis/therapy
• Stomatitis/veterinary

• R21 DE024711 NIDCR NIH HHS
• T32 OD011147 NIH HHS
• 1R21DE024711-01 NIDCR NIH HHS