Allogeneic MSC Research Articles

Isolation and Characterization of Canine Adipose-Derived Mesenchymal Stromal Cells: Considerations in Translation from Laboratory to Clinic.

In allogeneic MSC implantation, the cells are isolated from a donor different from the recipient. When tested, allogeneic MSCs have several advantages over autologous ones: faster cell growth, sufficient cell concentration, and readily available cells for clinics. To ensure the safe and efficient use of allogeneic MSCs in clinics, the MSCs need to be first tested in vitro. With this study, we paved the way by addressing the in vitro aspects of canine adipose-derived MSCs, considering the limited studies on the clinical use of canine cells. We isolated cAD-MSCs from canine falciform ligament fat and evaluated their viability and proliferation using an MTS assay. Then, we characterized the MSC-specific antigens using immunophenotyping and immunofluorescence and demonstrated their potential for in vitro differentiation. Moreover, we established shipping and cryobanking procedures to lead the study to become an off-the-shelf therapy. During expansion, the cells demonstrated a linear increase in cell numbers, confirming their proliferation quantitatively. The cells showed viability before and after cryopreservation, demonstrating that cell viability can be preserved. From a clinical perspective, the established shipping conditions demonstrated that the cells retain their viability for up to 48 h. This study lays the groundwork for the potential use of allogeneic cAD-MSCs in clinical applications.

Induced Pluripotent Stem Cell-Derived Mesenchymal Stromal Cells Promote Muscle Regeneration in a Diabetic Mouse Model of Critical Limb Threatening Ischemia

Critical limb threatening ischemia (CLTI), the end stage of peripheral arterial disease (PAD), is diagnosed in 500,000 patients each year, often results in amputation, and has a ~50% 5-year mortality rate. Diabetic CLTI patients experience especially high morbidity and mortality, and no effective non-surgical therapy exists for this population. Our Phase II MOBILE trial demonstrated that autologous bone marrow nucleated cells were unable to prevent amputations in diabetic patients; however, data from a Phase I trial shows that allogeneic bone marrow-derived mesenchymal stromal cells (BMD-MSC) stimulated angiogenesis in ischemic muscle, including diabetics. While allogeneic MSC may be an effective cell preparation to treat diabetic CLTI, passaging-related cell senescence prevents generation of sufficient cell numbers for therapeutic use. The development of induced pluripotent stem cell (iPSC)-derived MSC overcomes cell senescence issues and offers the possibility of genetic modifications to enhance cell function. The current study was designed to determine potential mechanisms by which iPSC-MSC stimulate muscle regeneration in a rodent CLTI model.
 The CLTI mouse model was created by ligation/excision of the femoral artery in male polygenic diabetic TallyHo mice. Mice with intramuscular administration of iPSC-MSC displayed positive indicators of muscle regeneration compared to vehicle control mice. Real-time PCR performed with gastrocnemius muscle obtained 7- or 30-days post iPSC-MSC injection showed an increase in mRNA expression for MyH3, MyoD1, Mrc1, FoxP3, and VEGF-A vs. vehicle treated muscle, indicating promotion of muscle regeneration, M2-biased macrophage expression, T regulatory cell (Treg) expansion, and vascular proliferation. Downregulation of the NADPHoxidase subunit p47phox indicated a decrease in oxidative stress in the treated mice. The results are consistent with iPSC-MSC promotion of muscle regeneration via a Treg mediated stimulation of the M1-M2 macrophage phenotypic shift. Thus, human iPSC-MSC could be an effective treatment to stimulate muscle regeneration and ameliorate CLTI in diabetic patients.

Real-world data suggest effectiveness of the allogeneic mesenchymal stromal cells preparation MSC-FFM in ruxolitinib-refractory acute graft-versus-host disease

BackgroundPatients with steroid-refractory acute graft-versus-host disease (aGvHD) not tolerating/responding to ruxolitinib (RR-aGvHD) have a dismal prognosis.MethodsWe retrospectively assessed real-world outcomes of RR-aGvHD treated with the random-donor allogeneic MSC preparation MSC-FFM, available via Hospital Exemption in Germany. MSC-FFM is provided as frozen cell dispersion for administration as i.v. infusion immediately after thawing, at a recommended dose of 1–2 million MSCs/kg body weight in 4 once-weekly doses. 156 patients, 33 thereof children, received MSC-FFM; 5% had Grade II, 40% had Grade III, and 54% had Grade IV aGvHD. Median (range) number of prior therapies was 4 (1–10) in adults and 7 (2–11) in children.ResultsThe safety profile of MSC-FFM was consistent with previous reports for MSC therapies in general and MSC-FFM specifically. The overall response rate at Day 28 was 46% (95% confidence interval [CI] 36–55%) in adults and 64% (45–80%) in children; most responses were durable. Probability of overall survival at 6, 12 and 24 months was 47% (38–56%), 35% (27–44%) and 30% (22–39%) for adults, and 59% (40–74%), 42% (24–58%) and 35% (19–53%) for children, respectively (whole cohort: median OS 5.8 months).ConclusionA recent real-world analysis of outcomes for 64 adult RR-aGvHD patients not treated with MSCs reports survival of 20%, 16% and 10% beyond 6, 12 and 24 months, respectively (median 28 days). Our data thus suggest effectiveness of MSC-FFM in RR-aGvHD.

Real-World Data Suggest Effectiveness of Allogeneic Mesenchymal Stromal (MSC-FFM) Cells in Ruxolitinib-Refractory Acute Graft-Versus-Host Disease

Introduction: Acute graft-versus-host disease (aGvHD) remains the leading cause of treatment-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Current first-line treatment of aGvHD is with high-dose corticosteroids, the standard for steroid-refractory aGvHD (SR-aGvHD) is the Janus kinase (JAK) inhibitor ruxolitinib. Outcomes for patients with ruxolitinib-refractory or -intolerant aGvHD (RR-aGvHD) are poor. Thus in a recent real-world study of adult patients with RR-aGvHD (Abedin BJH 2021) median survival was 28 days (21 days for ruxolitinib refractoriness, 50 days for ruxolitinib intolerance), the probability of overall survival (OS) at 6, 12, and 24 months were about 20%, 16%, and 10%, respectively. We assessed real-world outcomes of patients with RR-aGvHD treated with the random-donor allogeneic MSC preparation “MSC-FFM,” available via Hospital Exemption in Germany. Patients: Between December 2017 and February 2023, 156 patients, including 33 children and adolescents (<18 years of age), received MSC-FFM for RR-aGvHD. Thirty-two German sites contributed 139 patients, while the remaining 17 patients came from seven transplant centers in France, Hungary, Norway, Sweden, and Switzerland. The adult cohort (n=123) consisted of 41% females, with an age range of 19 to 79 years (median 55 years). Except for one patient, all had been diagnosed with malignant diseases (missing information, n=3). Among the adult patients with malignant diseases, 88% (n=105) received HSCT for acute myeloid leukemia (AML), advanced myelodysplastic syndrome, myeloproliferative neoplasm or lymphoma, and 12% (n=15) for acute lymphoblastic leukemia (ALL). In the pediatric cohort (n=33), 48% of patients were females, with an age range of 0 to 17 years (median 9 years). Overall, 58% of pediatric patients (n=19) had malignant diseases as the indication for allogeneic HSCT, 42% (n=8) having ALL and 32% (n=6) with AML. The remaining 42% of pediatric patients (n=14) had non-malignant diseases as the indication for HSCT. Of the adult patients, 6 (4.9%) had grade II, 52 (42.3%) had grade III, and 63 (51.2%) had grade IV aGvHD, with no specification reported for 2 patients (1.6%). In children, 2 (6.1%) had grade II, 10 (30.3%) had grade III, and 21 (63.6%) had grade IV Treatment: MSC-FFM is manufactured from pooled bone marrow mononuclear cells from eight HLA-disparate healthy donors. MSCs are selected by plastic adherence, expanded until the end of passage 3, then frozen in saline-albumin with DMSO. The recommended dosing for MSC-FFM is 1-2 million cells/kg body weight (BW), for four weekly doses. The median dose administered was 1.18 million cells/kg BW, with a median number of four doses and a median inter-dose interval of 7 days. Results: Safety: Tolerability of MSC-FFM was good, with only five adverse drug reactions reported in three adult patients (chills, BK virus cystitis, increase in C-reactive protein [reported twice in one patient], nausea) and did not result in cessation of MSC treatment or dose reductions. Response: The overall response rate at day +28 was 49% (95%-CI: 41-58%), with 45% (36-55%) in adults and 64% (45-80%) in children. Most responses were durable, resulting in an overall response rate of 49% (41-57%) for both adults and children at 2 months, and 40% (31-48%) at 6 months. Survival: Overall survival at 6, 12, and 24 months was 47% (38-56%), 35% (27-44%), and 29% (21-38%) for adults, and 59% (40-74%), 42% (24-58%), and 37% (19-54%) for children, respectively (Table 1). Median overall survival was 5.8 months. These outcomes compare favourably to published overall survival estimates for adult RR-aGvHD patients not treated with MSC-FFM (Abedin BJH, see above). Summary: The unique MSC-preparation MSC-FFM appears to be effective against RR-aGvHD.

Mesenchymal stromal cell therapy for feline chronic gingivostomatitis: Long term experience.

Mesenchymal stromal cells (MSC) therapy has emerged as a potential treatment option for refractory FCGS. However, there is a lack of long-term data on the use of MSC therapy in cats. This study aimed to evaluate the long-term safety and efficacy of MSC therapy for FCGS and investigate potential factors associated with treatment outcomes. This study was a retrospective evaluation of 38 client-owned cats with refractory FCGS who received MSC therapy. Medical records, histopathology, and the Stomatitis Activity Disease Index (SDAI) were reviewed. Correlations of the long-term follow-up success rates with SDAI and cell line type used were conducted. A client survey was also performed to assess side effect occurrence, quality-of-life following treatment, and overall treatment satisfaction. Long-term follow-up ranged from 2 to 9 years post-MSC treatment. The overall positive response rate to MSC treatment was 65.5%, with 58.6% of cats exhibiting permanent improvement or cure. Adverse effects occurring during or immediately after treatment were noted in 34.2% of cases, the majority being transient, self-resolving transfusion-like reactions. No long-term adverse events were noted. No significant correlation in outcome was detected between allogeneic and autologous MSC treatment (p = 0.871) or the severity of the SDAI at entry (p = 0.848) or exit (p = 0.166), or the delta SDAI between entry and exit (p = 0.178). The status 6 months (none to partial improvement vs. substantial improvement to resolution) post-therapy was a predictor of long-term response (value of p < 0.041). Most clients were satisfied with the treatment and outcomes, with 90.6% willing to pursue treatment again, given a similar situation. The results of this study support the use of both autologous and allogeneic MSC as an efficacious and safe therapeutic option for refractory FCGS.

FLIM imaging revealed spontaneous osteogenic differentiation of stem cells on gradient pore size tissue-engineered constructs

BackgroundThere is an urgent clinical need for targeted strategies aimed at the treatment of bone defects resulting from fractures, infections or tumors. 3D scaffolds represent an alternative to allogeneic MSC transplantation, due to their mimicry of the cell niche and the preservation of tissue structure. The actual structure of the scaffold itself can affect both effective cell adhesion and its osteoinductive properties. Currently, the effects of the structural heterogeneity of scaffolds on the behavior of cells and tissues at the site of damage have not been extensively studied.MethodsBoth homogeneous and heterogeneous scaffolds were generated from poly(L-lactic acid) methacrylated in supercritical carbon dioxide medium and were fabricated by two-photon polymerization. The homogeneous scaffolds consist of three layers of cylinders of the same diameter, whereas the heterogeneous (gradient pore sizes) scaffolds contain the middle layer of cylinders of increased diameter, imitating the native structure of spongy bone. To evaluate the osteoinductive properties of both types of scaffold, we performed in vitro and in vivo experiments. Multiphoton microscopy with fluorescence lifetime imaging microscopy was used for determining the metabolic states of MSCs, as a sensitive marker of cell differentiation. The results obtained from this approach were verified using standard markers of osteogenic differentiation and based on data from morphological analysis.ResultsThe heterogeneous scaffolds showed improved osteoinductive properties, accelerated the metabolic rearrangements associated with osteogenic differentiation, and enhanced the efficiency of bone tissue recovery, thereby providing for both the development of appropriate morphology and mineralization.ConclusionsThe authors suggest that the heterogeneous tissue constructs are a promising tool for the restoration of bone defects. And, furthermore, that our results demonstrate that the use of label-free bioimaging methods can be considered as an effective approach for intravital assessment of the efficiency of differentiation of MSCs on scaffolds.

Alloreactivity of Allogeneic Mesenchymal Stem/Stromal Cells and Other Cellular Therapies: A Concise Review.

Cellular therapies, deemed live medicine, have brought a wave of new generation biological therapies to treat previously untreatable diseases such as cancers and degenerative diseases like osteoarthritis. These cellular therapies have gained significant recognition in clinical research. The area has been further strengthened with the approval of Chimeric Antigen Receptor added on T cells (CAR-T) therapies by the regulatory authorities USA's Food and Drugs Administration (FDA), European Medical Agency (EMA), the Australian Therapeutic Goods Administration (TGA), and in many countries in 2017 to treat hematological cancers. Another milestone was achieved when allogeneic Mesenchymal Stem Cell- (MSC-) based therapy was approved by the EMA to treat Chrohn's disease in 2018. Allogeneic donor-derived MSC therapies in particular hold great promise and real hope because of their ‘off-the shelf' availability and accessibility for patients in need of urgent treatment. So far, thousands of clinical trials have explored the safety and efficacy of both autologous and allogeneic cell therapies, deeming them safe, however with varying degrees of efficacy. In the current pandemic, clinical trials have begun in many parts of the world to treat severe cases of COVID with MSCs. However, the risk of tissue rejection and the development of undesirable effects due to alloreactivity of allogeneic cells are currently not adequately addressed. Therefore, this warrants careful investigation and detailed reporting of such events by clinical researchers. This review aims at discussing the current landscape of approved allogeneic MSCs along with a few other cellular therapies. We explore any possible reactivity reported to inform the readers of any safety concern and on the efficacy of such therapies.

Immune response to allogeneic equine mesenchymal stromal cells

BackgroundMesenchymal stromal cells (MSCs) are believed to be hypoimmunogeneic with potential use for allogeneic administration.MethodsBone marrow was harvested from Connemara (n = 1), Standardbred (n = 6), and Thoroughbred (n = 3) horses. MSCs were grouped by their level of expression of major histocompatibility factor II (MHC II). MSCs were then sub-grouped by those MSCs derived from universal blood donor horses. MSCs were isolated and cultured using media containing fetal bovine serum until adequate numbers were acquired. The MSCs were cultured in xenogen-free media for 48 h prior to use and during all assays. Autologous and allogeneic MSCs were then directly co-cultured with responder leukocytes from the Connemara horse in varying concentrations of MSCs to leukocytes (1:1, 1:10, and 1:100). MSCs were also cultured with complement present and heat-inactivated complement to determine whether complement alone would decrease MSC viability. MSCs underwent haplotyping of their equine leukocyte antigen (ELA) to determine whether the MHC factors were matched or mismatched between the donor MSCs and the responder leukocytes.ResultsAll allogeneic MSCs were found to be ELA mismatched with the responder leukocytes. MHC II-low and universal blood donor MSCs caused no peripheral blood mononuclear cell (PBMC) proliferation, no increase in B cells, and no activation of CD8 lymphocytes. Universal blood donor MSCs stimulated a significant increase in the number of T regulatory cells. Neutrophil interaction with MSCs showed that universal blood donor and MHC II-high allogeneic MSCs at the 6 h time point in co-culture caused greater neutrophil activation than the other co-culture groups. Complement-mediated cytotoxicity did not consistently cause MSC death in cultures with active complement as compared to those with inactivated complement. Gene expression assays revealed that the universal blood donor group and the MHC II-low MSCs were more metabolically active both in the anabolic and catabolic gene categories when cultured with allogeneic lymphocytes as compared to the other co-cultures. These upregulated genes included CD59, FGF-2, HGF, IDO, IL-10, IL-RA, IL-2, SOX2, TGF-β1, ADAMSTS-4, ADAMSTS-5, CCL2, CXCLB/IL-8, IFNγ, IL-1β, and TNFα.ConclusionsMHC II-low MSCs are the most appropriate type of allogeneic MSC to prevent activation of the innate and cell-mediated component of the adaptive immune systems and have increased gene expression as compared to other allogeneic MSCs.

Development and investigational new drug application of mesenchymal stem/stromal cells products in China.

Mesenchymal stem/stromal cells (MSCs) have broad application prospects for regenerative medicine due to their self‐renewal, high plasticity, ability for differentiation, and immune response and modulation. Interest in turning MSCs into clinical applications has never been higher than at present. Many biotech companies have invested great effort from development of clinical grade MSC product to investigational new drug (IND) enabling studies. Therefore, the growing demand for publication of MSC regulation in China necessitates various discussions in accessible professional journals. The National Medical Products Administration has implemented regulations on the clinical application of MSCs therapy. The regulations for MSCs products as drug have been updated in recent years in China. This review will look over the whole procedure in allogeneic MSC development, including regulations, guidance, processes, quality management, pre‐IND meeting, and IND application for obtaining an approval to start clinical trials in China. The review focused on process and regulatory challenges in the development of MSCs products, with the goal of providing strategies to meet regulatory demands. This article describes a path for scientists, biotech companies, and clinical trial investigators toward the successful development of MSC‐based therapeutic product.

INTRAOVARIAN INJECTION OF ALLOGENEIC MESENCHYMAL STEM CELLS: FEASIBILITY AND SAFETY ASSESSMENT IN BOVINES

<h3>Background</h3> Ovum pick-up (OPU) is a technique widely used for production of bovine embryos in-vitro. However, continuous OPU can be associated with the appearance of often irreversible ovarian lesions. The possibility of using stem cell therapy for treatment of infertility both in animals and in humans is currently under investigation, but the safety of intraovarian infusion of stem cells in bovines has not been established at this point. Therefore, in the present study we determined the feasibility and safety of intraovarian application of allogeneic MSC derived from adipose tissue of healthy cows. <h3>Methods</h3> Two OPU procedures were executed 15 days apart. Immediately following the second OPU, 2.5 million allogeneic MSCs were injected to the ovarian cortex of healthy nelore (n=5) and girolando (N=5) cows. The animals were subsequently evaluated by ultrasonography and clinical examination at 24, 48 and 72 hs post MSC injection. At 15, 30 and 45 days post MSC injection, new OPU procedures were executed and the number of viable oocytes collected, and rate of embryo production were determined. <h3>Results</h3> No clinical nor ultrasonographic alterations were detected in treated animals. Furthermore, similar numbers of viable oocytes, embryos produced, and rate of embryo production before and after MSC application were observed. <h3>Conclusion</h3> Based on these data, it can be concluded that the intra-ovarian application of 2.5 million adipose-derived MSC is safe. Future steps include the MSC treatment of individuals which present ovarian degeneration or lesions. <h3>Financial support</h3> This work was supported by CNPq, CAPES, FAPDF, FAPESP and Universidade of Brasilia.

Impairment of Tissue-Resident Mesenchymal Stem Cells in Chronic Ulcerative Colitis and Crohn's Disease.

Little is known about the presence and function of tissue-resident mesenchymal stem cells [MtSCs] within the gastrointestinal mucosa in health and inflammatory bowel disease [IBD]. The contribution of MtSCs to the generation of inflammatory fibroblasts during IBD is also poorly understood. We hypothesized that IBD-MtSCs are impaired and contribute to the generation of the pathological myofibroblasts in IBD. In a cohort of clinically and endoscopically active IBD patients and normal controls, we used quantitative RT-PCR and stem cell differentiation assays, as well as confocal microscopy, to characterize MtSCs. Expression of two stem cell markers, Oct4 and ALDH1A, was increased in the inflamed IBD colonic mucosa and correlated with an increase of the mesenchymal lineage marker Grem1 in ulcerative colitis [UC], but not Crohn's disease [CD]. Increased proliferation and aberrant differentiation of Oct4+Grem1+ MtSC-like cells was observed in UC, but not in CD colonic mucosa. In contrast to normal and UC-derived MtSCs, CD-MtSCs lose their clonogenic and most of their differentiation capacities. Our data also suggest that severe damage to these cells in CD may account for the pathological PD-L1low phenotype of CD myofibroblasts. In contrast, aberrant differentiation of MtSCs appears to be involved in the appearance of pathological partially differentiated PD-L1high myofibroblasts within the inflammed colonic mucosa in UC. Our data show, for the first time, that the progenitor functions of MtSCs are differentially impaired in CD vs UC, providing a scientific rationale for the use of allogeneic MSC therapy in IBD, and particularly in CD.

Prognostic Factors for Clinical Response in Systemic Lupus Erythematosus Patients Treated by Allogeneic Mesenchymal Stem Cells.

Systemic lupus erythematosus (SLE) is an autoimmune disease with a broad range of clinical manifestations and a heterogeneous disease course. There is no cure for SLE, but current standard pharmacotherapies can improve disease prognosis in most patients. However, some patients are refractory to conventional treatments and require alternative treatment options. The present study is aimed at identifying predictors of clinical response to allogeneic bone marrow-derived or umbilical cord-derived mesenchymal stem cell (BM-/UC-MSC) transplant in SLE. All adult patients identified in the Nanjing database with an SLE Disease Activity Index (SLEDAI) score ≥ 8 at baseline that had undergone MSC transplant and who had at least 1 year of follow-up after one or two successive intravenous injections of allogeneic BM-/UC-MSCs (1 million/kg) were analyzed. SLE symptoms and SLEDAI were assessed at baseline and during follow-up to determine low disease activity (LDA) and clinical remission (CR) at 1, 3, 6, and 12 months. Sixty-nine patients were included in the study, with a median (range) SLEDAI of 13 (8-34) at baseline. Among the 69 patients, 40 (58%) achieved LDA and 16 (23%) achieved CR with a SLEDAI of 9 (4–20), 8 (0-16), 6 (0-18), and 5 (0-18) after 1, 3, 6, and 12 months, respectively. Older age (p = 0.006) and no arthralgia/arthritis at baseline (p = 0.03) were associated with a higher rate of LDA. Achieving CR was associated with older age (p = 0.033), no arthralgia/arthritis at baseline (p = 0.001), and no prior use of cyclophosphamide (p = 0.003) or hydroxychloroquine (p = 0.016). Future studies using unique immunosuppressive regimens and allogeneic MSC sources will further elucidate determinants of clinical response to MSC transplant in SLE.

Mesenchymal Stem Cell Therapy in Osteoarthritis and Regenerative Medicine.

Mesenchymal Stem Cell Therapy in Osteoarthritis and Regenerative Medicine.

95 - Long and short-term stability of frozen and thawed autologous and allogeneic MSC used in multiple clincal IND protocols

95 - Long and short-term stability of frozen and thawed autologous and allogeneic MSC used in multiple clincal IND protocols

80 - Phase 1 safety outcomes of mesenchymal stromal stem cell therapy in pateints with low and intermediate-1 ipss risk myelodysplastic syndrome

Myelodysplastic syndrome (MDS) is a haematological disorder of bone marrow failure which presents with low blood counts. The incidence is increasing in developed countries due to population aging. The prognosis for patients with MDS is defined by risk classification systems such as the International Prognostic Scoring System (IPSS). In patients with low or intermediate-1 (lower) risk IPSS MDS, standard care is supportive. Another treatment is immunotherapy. Allogeneic MSC infusion represents a novel immunotherapy in MDS with tolerable side effect profile. We designed a phase 1 study to assess the safety of MSC infusion in a population of lower risk MDS patients.

Abstract 8: Effectiveness of Combination Allogeneic Stem Cells in a Novel Large Animal Model of Chronic Kidney Disease-induced Heart Failure With Preserved Ejection Fraction (HFpEF)

Background: Chronic Kidney Disease (CKD) is an independent risk factor for cardiovascular morbidity and mortality. Left ventricular (LV) hypertrophy and heart failure with preserved ejection fraction (HFpEF) are the primary manifestations of the cardiorenal syndrome in 60 to 80% of CKD patients. Therapies that improve morbidity and mortality in HFpEF are lacking. Stem cell therapy reduces fibrosis, increases neovascularization, and promotes cardiac repair in ischemic and non-ischemic cardiomyopathies. We hypothesized that stem cell treatment ameliorates HFpEF in a CKD model. Methods: Yorkshires pigs (n=27) underwent 5/6 nephrectomy via renal artery embolization and 4-weeks later received either: allogeneic (allo-) MSC (10х10 6 ), allo-kidney c-kit + cells (c-kit; 10х10 6 ), combination (MSC+c-kit; 1:1 ratio [5х10 6 each]), or placebo (each n=5). Cell therapy was delivered via the patent renal artery. Kidney function, renal and cardiac MRI, and PV loops were measured at baseline, and at 4- and 12-weeks (euthanasia) post-embolization. Results: The CKD model was confirmed by increased creatinine and BUN and decreased GFR. Mean arterial pressure (MAP) was not different between groups from baseline to 4 weeks (p=0.7). HFpEF was demonstrated at 4 weeks by increased LV mass (20.3%; p= 0.0001), wall thickening (p&lt;0.008), EDP (p=0.01), EDPVR (p=0.005), and arterial elastance (p=0.03), with no change in EF. Diffuse intramyocardial fibrosis was evident in histological analysis and delayed enhancement MRI imaging. After 12 weeks, there was a significant difference in MAP between groups (p=0.04), with an increase in the placebo group (19.97± 8.65 mmHg, p=0.08). GFR significantly improved in the combination group (p=0.033). EDV increased in the placebo (p=0.009) and c-kit (p=0.004) groups. ESV increased most in the placebo group (7.14±1.62ml; p=0.022). EF, wall thickness, and LV mass did not differ between groups at 12 weeks. Conclusion: A CKD large animal model manifests the characteristics of HFpEF. Intra-renal artery allogeneic cell therapy was safe. A beneficial effect of cell therapy was observed in the combination and MSC groups. These findings have important implications on the use of cell therapy for HFpEF and cardiorenal syndrome.

Chondrogenic Differentiation Capacity of Human Umbilical Cord Mesenchymal Stem Cells with Platelet Rich Fibrin Scaffold in Cartilage Regeneration (In Vitro Study)

Background: Human umbilical cord mesenchymal stem cell is a promising source of allogenous MSC with great chondrogenic differentiation capacity. Meanwhile, platelet rich fibrin (PRF) is a natural fibrin matrix, rich in growth factors, forming a smooth and flexible fibrin network, supporting cytokines and cell migration, thus can be used as a scaffold that facilitate the differentiation of MSC. However, the differential capability of MSC cultured in PRF was still poorly understood. Method: We studied in vitro differentiation potential of MSC cultured in PRF by evaluating several markers such as FGF 18, Sox 9, type II collagen, aggrecan in 3 different culture medium. Result: The result showed that there was positive expression of FGF 18, Sox 9, type II collagen, aggrecan in all medium of in vitro culture. Conclusion: MSC cultured from human umbilical cord had the capacity of chondrogenic differentiation and able to produce cartilage extracellular matrix in vitro which means that hUCMSC is a potential allogeneic MSC for cartilage regeneration.

42 - Allogeneic Cord-Derived MSC Infusion is Safe and Improves Metabolic Functions of Uncontrolled Diabetes Patients

42 - Allogeneic Cord-Derived MSC Infusion is Safe and Improves Metabolic Functions of Uncontrolled Diabetes Patients

The challenges and promises of allogeneic mesenchymal stem cells for use as a cell-based therapy.

Mesenchymal stem cells (MSCs) are ideal for cell-based therapy in various inflammatory diseases because of their immunosuppressive and tissue repair properties. Moreover, their immunosuppressive properties and low immunogenicity contribute to a reduced or weakened immune response elicited by the implantation of allogeneic MSCs compared with other cell types. Therefore, implantation of allogeneic MSCs may be a promising cell-based therapy. In this review, we first summarize the unique advantages of allogeneic MSCs for therapeutic applications. Second, we critically analyze the factors influencing their therapeutic effects, including administration routes, detection time-points, disease models, differentiation of MSCs in vivo, and timing and dosage of MSC administration. Finally, current approaches to allogeneic MSC application are discussed. In conclusion, allogeneic MSCs are a promising option because of their low immunogenicity and immunosuppressive and tissue repair capabilities. Further investigations are needed to enhance the consistency and efficacy of MSCs when used as a cell-based therapy in inflammatory diseases as well as for tissue repair.

Mesenchymal stromal (stem) cells to improve solid organ transplant outcome: lessons from the initial clinical trials.

Discuss the recent progress on the clinical use of mesenchymal stromal (stem) cells (MSC) in solid organ transplantation (SOT). Tissue repair and immunomodulatory properties have been recognized for MSC obtained from different human tissues. MSC-based therapy has been proposed to reduce ischemia-reperfusion injury and to promote immune tolerance. The results of recent clinical trial support the safety and promising effects of autologous and allogeneic MSC in SOT. Collectively, the use of MSC in recipients of living donor kidney transplantation was associated with improved graft function, reduced rejection, ability to omit induction and/or lower maintenance immunosuppression regimen, as well as to treat rejection episodes. We are living in very exciting times with the implementation of novel clinical trials aimed at establishing safety, feasibility and efficacy of cellular therapies including MSC to improve SOT outcomes. The results of the initial clinical trials support the safety of MSC-based therapy and justifying cautious optimism for the immediate future.