Allogeneic Human Mesenchymal Stem Cells Research Articles

Novel Treatment Options for Knee Cartilage Defects in 2023.

Articular cartilage lesions are a common injury that have become increasingly treatable with joint preservation procedures. Well-documented allograft and cellular treatments for these lesions are detailed elsewhere in this volume. This article discusses three new unique options for addressing these defects taking three different paths to address these complex injuries. Agili-C is an existing FDA- and EMEA-approved option using an acellular aragonite-based scaffold to treat both chondral and osteochondral lesions, with or without concurrent arthritis. Cartistem is a stem-cell-based product composed of culture-expanded allogeneic human umbilical cord blood-derived mesenchymal stem cells and hyaluronic acid hydrogel, which is in its final clinical trial stages in the United States, but already has regulatory approval in Korea. IMPACT and RECLAIM studies have shown the safety and efficacy of a new one-stage procedure utilizing autologous chondrons combined with allogeneic mesenchymal stem cells (MSCs) that can provide another effective single-stage treatment option.

Preclinical assessments of safety and tumorigenicity of very high doses of allogeneic human umbilical cord mesenchymal stem cells

Human umbilical cord-mesenchymal stem cells (hUC-MSCs) have been widely investigated as a new therapeutic agent to treat injuries and inflammatory-mediated and autoimmune diseases. Previous studies have reported on the safety of low-dose infusion of hUC-MSCs, but information on the cell behaviour at higher doses and frequency of injection of the cells remains uncertain. The aim of the present study was to demonstrate the safety and efficacy of hUC-MSCs by Cytopeutics® (Selangor, Malaysia) from low to an extremely high dose in different monitoring periods in healthy BALB/c mice as well as assessing the tumorigenicity of the cells in B-NDG SCID immunocompromised mice. Umbilical cord from two healthy human newborns was obtained and the isolation of the hUC-MSCs was performed based on previous established method. Assessment of the cells at different doses of single or multiple administrations was performed on healthy BALB/c mice in dose range finding, sub-acute (7 d and 28 d) and sub-chronic periods (90 d). Tumorigenicity potential of Cytopeutics® hUC-MSCs was also evaluated on B-NDG immunocompromised mice for 26 wk. Single or multiple administrations of Cytopeutics® hUC-MSCs up to 40 × 106 cells per kilogramme of body weight (kg BW) were found to have no adverse effect in terms of clinical symptoms, haematology and other laboratory parameters, and histology examination in healthy BALB/c mice. hUC-MSCs were also found to reduce pro-inflammatory cytokines (IL-6 and TNF-α) in a dose-dependent manner. No sign of tumor formation was observed in B-NDG mice in the 26-wk tumorigenicity assessment. Single or multiple administration of allogenic Cytopeutics® hUC-MSCs was safe even at very high doses, is non-tumorigenic and did not cause adverse effects in mice throughout the evaluation periods. In addition, Cytopeutics® hUC-MSCs exhibited immunomodulatory effect in a dose-dependent manner.

Prognostic Factors for Clinical Outcome and Cartilage Regeneration after Implantation of Allogeneic Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Large-Sized Cartilage Defects with Osteoarthritis.

To analyze the prognostic factors for clinical outcomes and cartilage regeneration after the implantation of allogeneic human umbilical cord blood mesenchymal stem cell (hUCB-MSC) for treating large-sized cartilage defects with osteoarthritis. This study is a case-series with multiple subgroup analyses that divides the included patients into multiple subgroups based on various factors. Overall, 47 patients who underwent hUCB-MSC implantation were included. The patient-reported outcomes, magnetic resonance imaging (MRI), and second-look arthroscopy were used to assess the outcomes. Combined realignment surgery significantly correlated with clinical outcomes, particularly pain. No other factors significantly influenced the clinical outcomes in short-term period. Subgroups with large defect sizes or meniscal insufficiency showed significantly poor MRI and arthroscopy outcomes (MRI, P = 0.001, P = 0.001; arthroscopy, P = 0.032, P = 0.042). The logistic regression showed that patients with a 1 cm2 larger defect size were 1.91 times less likely to achieve favorable MRI outcomes (P = 0.017; odds ratio [OR], 1.91). Cut-off value to predict the poor outcome was >5.7 cm2 (area under the curve, 0.756). A cartilage defect size >5.7 cm2 was the major poor prognostic factor for cartilage regeneration on MRI (P = 0.010; OR, 17.46). If the postoperative alignment shifted by 1° opposite to the cartilage defect, it was 1.4 times more likely to achieve favorable MRI outcomes (P = 0.028; OR, 1.4). Combining realignment surgery showed a better prognosis for pain improvement. Cartilage defect size, meniscal function, and postoperative alignment are significant prognostic factors for cartilage regeneration. A cartilage defect size >5.7 cm2 was significantly related to poor cartilage regeneration.

Characterization of dynamical changes in vital signs during allogeneic human umbilical cord-derived mesenchymal stem cells infusion

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs), a kind of adult stem cell, were studied for clinical applications in regenerative medicine. To date, the safety evaluations of intravenous infusion of allogeneic hUC-MSCs were focused on fever, infection, malignancy, and death. However, the characteristics of dynamical changes in vital signs during hUC-MSCs infusion are largely unknown. In this study, twenty participants with allogeneic hUC-MSCs transplanted (MSC group) and twenty sex- and age-matched individuals with cardiovascular disease who treated with the equal volume of 0.9% normal saline were recruited (NS group). Heart rate, respiratory rate, oxygen saturation, systolic and diastolic blood pressure, and temperature were monitored at intervals of 15 min during infusion. Adverse events were recorded during infusion and within seven days after infusion. No adverse events were observed during and after infusion in both groups. Compared with the baseline, the mean systolic blood pressure (SBP) levels were significantly decreased at 15 min, 30 min, 45 min and 60 min in the MSC group (all P < 0.05) during infusion. In addition, SBP changed significantly from baseline during hUC-MSCs infusion when compared with that of NS group (P < 0.05). Repeated measures analysis of variance confirmed difference over time on the SBP levels (P < 0.05). Our results showed that the process of allogeneic hUC-MSCs intravenous infusion was safe and the vital signs were stable, whereas a slight decrease in SBP was observed.

A phase I study assessing the safety and tolerability of allogeneic mesenchymal stem cell infusion in adults with cystic fibrosis

BackgroundMesenchymal stem cells are of particular interest in cystic fibrosis (CF) as a potential therapeutic. Data from pre-clinical studies suggest that allogeneic bone marrow-derived human mesenchymal stem cells (hMSCs) may provide a new therapeutic treatment for CF lung disease by attenuating pulmonary inflammation while decreasing bacterial growth and enhancing antibiotic efficacy. MethodsFifteen adults with CF were enrolled in a phase 1 dose-escalation trial of a single intravenous infusion of hMSCs derived from bone marrow aspirates obtained from a single pre-clinically validated healthy volunteer donor. The study employed a 3+3 dose escalation design with subjects receiving a single, intravenous dose of either 1×106, 3×106, or 5×106 hMSCs/kg. Subjects were monitored inpatient for 24 hours and by outpatient visits and telephone calls for 12 months after the infusion. Safety and tolerability were evaluated by monitoring symptoms, patient reported outcome questionnaires, adverse events (AEs), physical exam findings, spirometry, and analyses of safety laboratories. Preliminary evidence for potential efficacy using inflammatory markers in the blood and sputum were also evaluated. ResultsNo dose-limiting toxicities, deaths or life-threatening adverse events were observed. Most AEs and serious adverse events (SAEs) were consistent with underlying CF. Vital signs, physical exam findings, spirometry and safety laboratory results showed no significant change from baseline. No trends over time were seen in serum or sputum inflammatory markers nor with clinical spirometry. ConclusionAllogeneic hMSC intravenous infusions were safe and well-tolerated in this phase 1 study and warrant additional clinical testing as a potential therapeutic for CF lung disease.

Ex Vivo Treatment with Allogenic Mesenchymal Stem Cells of a Healthy Donor on Peripheral Blood Mononuclear Cells of Patients with Severe Alopecia Areata: Targeting Dysregulated T Cells and the Acquisition of Immunotolerance.

Alopecia areata (AA) is an autoimmune condition related to the collapse of the immune privilege of hair follicles. Certain AA populations present severe clinical manifestations, such as total scalp hair or body hair loss and a treatment refractory property. The aim of this study was to assess the effects of allogenic human mesenchymal stem cells (hMSCs) from healthy donors on the peripheral blood mononuclear cells (PBMCs) of severe AA patients, with a focus on the change in the cell fraction of Th1, Th17, and Treg cells and immunomodulatory functions. PBMCs of 10 AA patients and eight healthy controls were collected. Levels of Th17, Th1, and Treg subsets were determined via flow cytometry at baseline, activation status, and after co-culturing with hMSCs. All participants were severe AA patients with SALT &gt; 50 and with a long disease duration. While the baseline Th1 and Treg levels of AA patients were comparable to those of healthy controls, their Th17 levels were significantly lower than those of the controls. When stimulated, the levels of CD4+IFN-γ+ T cells of the AA patients rose sharply compared to the baseline, which was not the case in those of healthy controls. The cell fraction of CD4+Foxp3+ regulatory T cells also abruptly increased in AA patients only. Co-culturing with allogenic hMSCs in activated AA PBMCs slightly suppressed the activation levels of CD4+INF-γ+ T cells, whereas it significantly induced the differentiation of CD4+Foxp3+ regulatory T cells. However, these changes were not prominent in the PBMCs of health controls. To examine the pathomechanisms, PBMCs of healthy donors were treated with IFN-γ to induce AA-like environment and then treated with allogenic grants and compared with ruxolitinib as a positive treatment control. hMSC treatment was shown to significantly inhibit the mRNA levels of proinflammatory cytokines, such as IFN-γ, TNF-α, IL-1α, IL-2R, IL-15, and IL-18, and chemokines, such as CCR7 and CCR10, in IFN-treated PBMCs. Interestingly, hMSCs suppressed the activation of JAK/STAT signaling by IFN in PBMCs with an effect that was comparable to that of ruxolitinib. Furthermore, the hMSC treatment showed stronger efficacy in inducing Foxp3, IL-10, and TGF-β mRNA transcription than ruxolitinib in IFN-treated PBMCs. This study suggests that allogenic hMSC treatments have therapeutic potential to induce immune tolerance and anti-inflammatory effects in severe AA patients.

The Combined Use of Platelet-Rich Plasma Clot Releasate and Allogeneic Human Umbilical Cord Mesenchymal Stem Cells Rescue Glucocorticoid-Induced Osteonecrosis of the Femoral Head.

Glucocorticoid-induced osteonecrosis of the femoral head (ONFH) is a refractory disease. The treatment options for ONFH, especially nonsurgical ones, merit further investigation. To evaluate the combinatorial therapeutic effects of platelet-rich plasma clot releasate (PRCR) and umbilical cord mesenchymal stem cells (UC-MSCs) on glucocorticoid-induced ONFH, a dexamethasone (DEX)-treated cell model and a high-dose methylprednisolone (MPS)-treated rat model were established. Cell counting kit-8 (CCK-8) assay was performed in vitro to determine the optimum dosage of PRCR for UC-MSC viability. The effects of PRCR, UC-MSCs, and PRCR + UC-MSCs on cell viability, apoptosis, migration, and differentiation capacities of DEX-treated bone marrow mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cell (HUVECs) were explored via Transwell assays. Western blotting was conducted to evaluate the expression levels of RUNX2, VEGF, caspase-3, and Bcl-2 in the coculture systems. Ultrasound-guided intra-articular PRCR, UC-MSCs, and PRCR + UC-MSC injections were performed on the ONFH model rats. Microcomputed tomography, histological and immunohistochemical analyses, tartrate-resistant acid phosphatase (TRAP) staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to assess the therapeutic effects of PRCR and UC-MSCs on bone loss and necrosis induced by high-dose MPS. Results of this study revealed that the in vitro application of PRCR, UC-MSCs, and PRCR + UC-MSCs reversed the impaired proliferation and migration capacities and resisted apoptosis of BMSCs and HUVECs induced by DEX. Moreover, the PRCR and UC-MSC application significantly improved the alkaline phosphatase (ALP) and alizarin red (ALR) staining of BMSCs and tube formation capacity of HUVECs and promoted the protein expression of RUNX2 in BMSCs and VEGF in HUVECs. Similarly, in the ONFH rat model, the intra-articular injection of UC-MSCs and PRCR improved the subchondral bone mass parameters; promoted the expression of ALP, RUNX2, and VEGF; suppressed osteoclast overactivity; and resisted cell apoptosis. The combination of PRCR and UC-MSCs shows promising therapeutic effects in treating glucocorticoid-induced ONFH. The current study provides important information on intra-articular therapy, paving the way for the clinical management of ONFH in the future.

Dry arthroscopy with a simple retraction technique for knee joint cartilage repair using allogenic human umbilical cord blood-derived mesenchymal stem cells

Mesenchymal stem cell treatment has become more widely available and has shown promising potential for the repair of knee articular cartilage defects. More recently, open arthrotomy has been performed via a para-patellar incision for cartilage repair using allogenic human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs). However, arthroscopy allows better visualization and leads to earlier gain of the range of motion and less scar formation than open arthrotomy, especially in the knee joint. In this study, we present an easy and effective technique for arthroscopic hUCB-MSCs implantation without any special equipment.

Abstract 9813: A Randomized, Double Blind, Clinical Trial to Evaluate Safety and Efficacy of Allogeneic Mesenchymal Human Stem Cells Infusion Therapy for Endothelial Dysfunction in Diabetic Subjects (ACESO)

Introduction: Endothelial dysfunction underlies the pathophysiology of cardiovascular disease (CVD) in patients with diabetes mellitus (DM), but no known effective therapies exist. The randomized, double-blind ACESO clinical trial evaluated the safety and efficacy of allogeneic human mesenchymal stem cells (allo-MSCs) infusion to target endothelial dysfunction in Type 2 DM subjects. Methods: An open label pilot phase (n=6) was followed by a blinded, randomized phase (n=10) study. DM subjects with endothelial dysfunction received a single peripheral intravenous infusion of either 20 or 100 million allo-MSCs (obtained from 3 healthy bone marrow donors) and followed for 1 yr. The primary endpoint was incidence of treatment-emergent serious adverse events (TE-SAE) within 1-month post-infusion. Secondary endpoints assessed endothelial function via endothelial progenitor cell-colony forming units (EPC-CFUs) and flow-mediated dilation (FMD%). Results: Participants had well-controlled DM, blood pressure, and kidney function (GFR ≥50 ml/min), and most were taking statins. The 6 pilot-phase participants were men (1 Asian, 5 non-Hispanic white) with mean (±SD) age of 69.3 (9.6) years. The 10 randomized participants were 5 men and 5 women (5 Hispanic, 3 non-Hispanic Black), with mean age of 60.9 (10.6) years. No TE-SAEs were reported. None of the patients in the pilot phase developed Panel Reactive Antibodies (PRAs). One randomized subject had a moderate increase in PRAs after infusion. Both treatment groups (20 and 100M allo-MSCs) in the pilot and randomized phases showed increased EPC-CFUs over time, particularly at 14 and 28 days post-infusion, that was sustained at 6-12 months. FMD data followed a trend rising above baseline and peaking at days 7 to 14, and then subsided to pre-infusion levels by 1 yr. Conclusion: Peripheral infusion of allo-MSCs for patients with DM and endothelial dysfunction is safe. Allo-MSCs improve EPCs and FMD within 14 to 28 days post-infusion, and the effect is sustained for 6 to 12 months. Larger clinical trials are warranted to assess the efficacy of allo-MSC therapy for cardiovascular outcomes in diabetic patients. Clinical Trial Registration: URL: https://www.clinicaltrials.gov.; Unique ID: NCT02886884

Stem cell restores thalamocortical plasticity to rescue cognitive deficit in neonatal intraventricular hemorrhage

Severe neonatal intraventricular hemorrhage (IVH) patients incur long-term neurologic deficits such as cognitive disabilities. Recently, the intraventricular transplantation of allogeneic human umbilical cord blood-derived mesenchymal stem cells (MSCs) has drawn attention as a therapeutic potential to treat severe IVH. However, its pathological synaptic mechanism is still elusive. We here demonstrated that the integration of the somatosensory input was significantly distorted by suppressing feed-forward inhibition (FFI) at the thalamocortical (TC) inputs in the barrel cortices of neonatal rats with IVH by using BOLD-fMRI signal and brain slice patch-clamp technique. This is induced by the suppression of Hebbian plasticity via an increase in tumor necrosis factor-α expression during the critical period, which can be effectively reversed by the transplantation of MSCs. Furthermore, we showed that MSC transplantation successfully rescued IVH-induced learning deficits in the sensory-guided decision-making in correlation with TC FFI in the layer 4 barrel cortex.

HUMAN UMBILICAL CORD-DERIVED MESENCHYMAL STEM CELLS OR MICROFRACTURES ASSOCIATED TO A COLLAGEN MATRIX FOR BILATERAL KNEE CHONDRAL LESIONS REPAIR: A CLINICAL COMPARATIVE STUDY

<h3>Backgroud</h3> Collagen matrix associated to microfractures is a recognized option for chondral lesions repair. However, microfractures damage the subchondral bone and recruit an undefined amount of cells, what can lead to poor quality tissue repair. Allogenic human umbilical cord-derived mesenchymal stem cells (HUC-MSC) showed ease to obtaining, inflammatory response control, no ethic issue, no immune response. These cells can be stored in large and defined amount and be available for one-step surgery, what could improve chondral repair when associated to collagen matrix. This study aimed to compare short-term outcomes of using HUC-MSC or microfractures associated to a collagen matrix for bilateral knee chondral lesions repair. <h3>Methods</h3> The study was approved by CONEP: 1.695.843 / CAEE: 56776716.1.1001.0020. In a prospective study, three patients (mean age of 40,6 years) with bilateral knee full-thickness chondral lesions were evaluated. As the study group (SG), the right knees were treated by collagen matrix plus HUC-MSC. As the control group (CG), the left knees were treated by collagen matrix plus microfractures. Chondral defects were located in the patella (2) and the trochlea (1), and mean size was 4,6 cm2 in the SG and 3,3 cm2 in the CG. All the HUC-MSC were obtained from donors with negative serology to infections. After in vitro expansion, the HUC-MSC had 97% viability; showed negative culture bacterial and/or fungi growth, absence of mycoplasma and endotoxins; flow cytometry analysis showed positive to CD90, CD105, CD29 and CD73 and negative to CD45, CD34, CD14, CD19 and HLA-DR and normal karyotype by GTG cytogenetic analysis. By knee arthrotomy, collagen matrix Chondro-Gide was implanted on the chondral defect on both groups. SG was associated to the injection of 40 × 10⁶ of HUC-MSC. In the CG, microfractures were performed before matrix implantation. KOOS, VAS and MRI results were compared pre and postoperatively. <h3>Results</h3> After 12 months of follow-up, KOOS and VAS scores were improved postoperatively in both groups as compared to a baseline. On the SG, all MRI showed signs of full-filling, smooth surface, complete integration to adjacent cartilage, and no bone edema. MRI showed the same findings on the CG, except one, and two knees showed bone edema. No adverse effects, rejection or complications were noted in both groups. <h3>Conclusion</h3> HUC-MSC associated to collagen matrix is a safe one-step procedure for knee chondral lesions repair and shows good outcomes when compared to collagen matrix plus microfractures in the short-term.

Allogenic Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Are More Effective Than Bone Marrow Aspiration Concentrate for Cartilage Regeneration After High Tibial Osteotomy in Medial Unicompartmental Osteoarthritis of Knee

The purpose of this study was to compare the outcome of cartilage regeneration between bone marrow aspirate concentrate (BMAC) augmentation and allogeneic human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) transplantation in high tibial osteotomy (HTO) with microfracture (MFX) for medial unicompartmental osteoarthritis (OA) of knee in the young and active patient. Between January 2015 and December 2019, the patients who underwent HTO and arthroscopy with MFX combined with BMAC or allogeneic hUCB-MSCs procedure for medial unicompartmental OA with kissing lesion which was shown full thickness cartilage defect (≥ International Cartilage Repair Society (ICRS) grade 3B) in medial femoral cartilage and medial tibial cartilage were include in this study. Retrospectively we compared clinical outcomes, including Hospital for Special Surgery (HSS) score, Knee Society Score (KSS) pain and function, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score between BMAC and hUCB-MSCs group at minimum of 1 year follow up. Also, second-look arthroscopy was performed simultaneously with removal of the plate after complete bone union. Cartilage regeneration was graded by International Cartilage Repair Society (ICRS) grading system at second-look arthroscopy. Radiologic measurement including Hip-Knee-Ankle (HKA) angle, posterior tibial slope angle, and correction angle were assessed. Out of 150 cases underwent HTO with MFX combined with BMAC or allogeneic hUCB-MSCs procedure for medial unicompartmental OA, 123 cases underwent plate removal and second-look arthroscopy after minimum 1 year after the HTO surgery. 74 cases were kissing lesion in medial femoral cartilage and medial tibial cartilage during initial HTO surgery. Finally, BMAC group comprising of 42 cases and hUCB-MSCs group comprising of 32 cases were retrospectively identified in patients who had kissing lesions and second look arthroscopies with minimum 1 year follow-up. At the final follow-up of mean 18.7 months (SD 4.6 months), clinical outcomes in both groups had improved. However, there were no significant differences between the IKDC, WOMAC, or KSS pain and function scores in the two groups (p>0.05). At second-look arthroscopy, ICRS grade was significantly better in the hUCB-MSC group than in the BMAC group in both medial femoral and medial tibial cartilage (p=0.001 for both). Average ICRS grade of the BMAC group improved from 3.9 preoperatively to 2.8 postoperatively. Average ICRS grade of the hUBC-MSC group improved from 3.9 preoperatively to 2.0 postoperatively. Radiologic findings comparing postoperative HKA angle, posterior tibial slope angle, and correction angle showed no significant differences between the groups (p>0.05). Therefore, it was found that the postoperative correction amount did not affect the postoperative cartilage regeneration results. We found that the hUCB-MSC procedure was more effective than the BMAC procedure for cartilage regeneration in medial unicompartmental knee OA even though the clinical outcomes improved regardless of which treatment was administered.

Establishment of a novel mesenchymal stem cell-based regimen for chronic myeloid leukemia differentiation therapy

Chronic myeloid leukemia (CML) is characterized by the accumulation of malignant and immature white blood cells which spread to the peripheral blood and other tissues/organs. Despite the fact that current tyrosine kinase inhibitors (TKIs) are capable of achieving the complete remission by reducing the tumor burden, severe adverse effects often occur in CML patients treated with TKIs. The differentiation therapy exhibits therapeutic potential to improve cure rates in leukemia, as evidenced by the striking success of all-trans-retinoic acid in acute promyelocytic leukemia treatment. However, there is still a lack of efficient differentiation therapy strategy in CML. Here we showed that MPL, which encodes the thrombopoietin receptor driving the development of hematopoietic stem/progenitor cells, decreased along with the progression of CML. We first elucidated that MPL signaling blockade impeded the megakaryocytic differentiation and contributed to the progression of CML. While allogeneic human umbilical cord-derived mesenchymal stem cells (UC-MSCs) treatment efficiently promoted megakaryocytic lineage differentiation of CML cells through restoring the MPL expression and activating MPL signaling. UC-MSCs in combination with eltrombopag, a non-peptide MPL agonist, further activated JAK/STAT and MAPK signaling pathways through MPL and exerted a synergetic effect on enhancing CML cell differentiation. The established combinational treatment not only markedly reduced the CML burden but also significantly eliminated CML cells in a xenograft CML model. We provided a new molecular insight of thrombopoietin (TPO) and MPL signaling in MSCs-mediated megakaryocytic differentiation of CML cells. Furthermore, a novel anti-CML treatment regimen that uses the combination of UC-MSCs and eltrombopag shows therapeutic potential to overcome the differentiation blockade in CML.

Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series

BackgroundAcute respiratory distress syndrome (ARDS) is a fatal complication of coronavirus disease 2019 (COVID-19). There are a few reports of allogeneic human mesenchymal stem cells (MSCs) as a potential treatment for ARDS. In this phase 1 clinical trial, we present the safety, feasibility, and tolerability of the multiple infusions of high dose MSCs, which originated from the placenta and umbilical cord, in critically ill COVID-19-induced ARDS patients.MethodsA total of 11 patients diagnosed with COVID-19-induced ARDS who were admitted to the intensive care units (ICUs) of two hospitals enrolled in this study. The patients were critically ill with severe hypoxemia and required mechanical ventilation. The patients received three intravenous infusions (200 × 106 cells) every other day for a total of 600 × 106 human umbilical cord MSCs (UC-MSCs; 6 cases) or placental MSCs (PL-MSCs; 5 cases).FindingsThere were eight men and three women who were 42 to 66 years of age. Of these, six (55%) patients had comorbidities of diabetes, hypertension, chronic lymphocytic leukemia (CLL), and cardiomyopathy (CMP). There were no serious adverse events reported 24–48 h after the cell infusions. We observed reduced dyspnea and increased SpO2 within 48–96 h after the first infusion in seven patients. Of these seven patients, five were discharged from the ICU within 2–7 days (average: 4 days), one patient who had signs of acute renal and hepatic failure was discharged from the ICU on day 18, and the last patient suddenly developed cardiac arrest on day 7 of the cell infusion. Significant reductions in serum levels of tumor necrosis factor-alpha (TNF-α; P < 0.01), IL-8 (P < 0.05), and C-reactive protein (CRP) (P < 0.01) were seen in all six survivors. IL-6 levels decreased in five (P = 0.06) patients and interferon gamma (IFN-γ) levels decreased in four (P = 0.14) patients. Four patients who had signs of multi-organ failure or sepsis died in 5–19 days (average: 10 days) after the first MSC infusion. A low percentage of lymphocytes (< 10%) and leukocytosis were associated with poor outcome (P = 0.02). All six survivors were well with no complaints of dyspnea on day 60 post-infusion. Radiological parameters of the lung computed tomography (CT) scans showed remarkable signs of recovery.InterpretationWe suggest that multiple infusions of high dose allogeneic prenatal MSCs are safe and can rapidly improve respiratory distress and reduce inflammatory biomarkers in some critically ill COVID-19-induced ARDS cases. Patients that develop sepsis or multi-organ failure may not be good candidates for stem cell therapy. Large randomized multicenter clinical trials are needed to discern the exact therapeutic potentials of MSC in COVID-19-induced ARDS.

Repeated subarachnoid administrations of allogeneic human umbilical cord mesenchymal stem cells for spinal cord injury: a phase 1/2 pilot study

Background aimsStem cell transplantation is a potential treatment for intractable spinal cord injury (SCI), and allogeneic human umbilical cord mesenchymal stem cells (hUC-MSCs) are a promising candidate because of the advantages of immune privilege, paracrine effect, immunomodulatory function, convenient collection procedure and little ethical concern, and there is an urgent need to develop a safe and effective protocol regarding their clinical application. MethodsA prospective, single-center, single-arm study in which subjects received four subarachnoid transplantations of hUC-MSCs (1 × 106 cells/kg) monthly and were seen in follow-up four times (1, 3, 6 and 12 months after final administration) was conducted. At each scheduled time point, safety and efficacy indicators were collected and analyzed accordingly. Adverse events (AEs) were used as a safety indicator. American Spinal Injury Association (ASIA) and SCI Functional Rating Scale of the International Association of Neurorestoratology (IANR-SCIFRS) total scores at the fourth follow-up were determined as primary efficacy outcomes, whereas these two indicators at the remaining time points as well as scores of pinprick, light touch, motor and sphincter, muscle spasticity and spasm, autonomic system, bladder and bowel functions, residual urine volume (RUV) and magnetic resonance imaging (MRI) were secondary efficacy outcomes. Subgroup analysis of primary efficacy indicators was also performed. ResultsSafety and efficacy assessments were performed on 102 and 41 subjects, respectively. Mild AEs involving fever (14.1%), headache (4.2%), transient increase in muscle tension (1.6%) and dizziness (1.3%) were observed following hUC-MSC transplantation and resolved thoroughly after conservative treatments. There was no serious AE. ASIA and IANR-SCIFRS total scores revealed statistical increases when compared with the baselines at different time points during the study, mainly reflected in the improvement of pinprick, light touch, motor and sphincter scores. Moreover, subjects showed a continuous and remarkable decrease in muscle spasticity. Regarding muscle spasm, autonomic system, bladder and bowel functions, RUV and MRI, data/imaging at final follow-up showed significant improvements compared with those at first collection. Subgroup analysis found that hUC-MSC transplantation improved neurological functions regardless of injury characteristics, including level, severity and chronicity. ConclusionsThe authors’ present protocol demonstrates that intrathecal administration of' allogeneic hUC-MSCs at a dose of 106 cells/kg once a month for 4 months is safe and effective and leads to significant improvement in neurological dysfunction and recovery of quality of life.

Allogeneic umbilical cord blood-derived mesenchymal stem cells combined with high tibial osteotomy: a retrospective study on safety and early results.

Cartilage repair performed as a single-stage procedure is an important advancement in the treatment of full-thickness cartilage injury and has potential for widespread clinical use. To investigate the short-term outcomes and cartilage regeneration after implantation of allogeneic human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in patients who received high tibial osteotomy (HTO) for symptomatic medial knee osteoarthritis. Patients underwent treatment of full-thickness chondral injury in the osteoarthritic knee with HTO and implantation of hUCB-MSCs and were followed prospectively for a minimum of oneyear. Ninety-three patients were followed for a mean 1.7years (range, 1.0-3.5). Median cartilage lesion size was 6.5cm2 (range, 2.0-12.8). Clinical outcomes were examined with patient-reported scoring instruments that consisted of the International Knee Documentation Committee (IKDC) subjective score, Western Ontario and McMaster University Osteoarthritis Index (WOMAC) score, Knee Society Score (KSS), and Hospital for Special Surgery (HSS) score. Cartilage regeneration was evaluated using the International Cartilage Repair Society (ICRS) cartilage repair assessment grading (CRA) system and the Koshino regeneration staging system in 49 patients who underwent secondlook arthroscopic assessment when their HTO plates were removed. At final follow-up, the median IKDC subjective score had significantly improved from 39.0 to 71.3; the WOMAC score from 44.5 to 11.0; the KSS pain and function scores from 29.8 to 43.2 and 61.0 to 81.2, respectively; and the HSS from 61.6 to 82.7 (p < 0.05). Pre-operative examination showed ICRS grade IV cartilage injury in all knees, and cartilage regeneration at 2nd look arthroscopy showed improvements (8.2% of patients improved to ICRS grade I, 69.3% to grade II, and 22.5% to grade III). Moreover, Koshino stage was B in 24.5% and C in 75.5% of patients (p < 0.05). Allogeneic hUCB-MSC implantation combined with HTO for medial knee osteoarthritis was safe and showed signs of cartilage status improvement. Furthermore, randomized controlled studies with a control group are necessary to determine the real effectiveness and indications of this new combined procedure for patients with osteoarthritis.

High tibial osteotomy with human umbilical cord blood-derived mesenchymal stem cells implantation for knee cartilage regeneration.

High tibial osteotomy (HTO) is a well-established method for the treatment of medial compartment osteoarthritis of the knee with varus deformity. However, HTO alone cannot adequately repair the arthritic joint, necessitating cartilage regeneration therapy. Cartilage regeneration procedures with concomitant HTO are used to improve the clinical outcome in patients with varus deformity. To evaluate cartilage regeneration after implantation of allogenic human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) with concomitant HTO. Data for patients who underwent implantation of hUCB-MSCs with concomitant HTO were evaluated. The patients included in this study were over 40 years old, had a varus deformity of more than 5°, and a full-thickness International Cartilage Repair Society (ICRS) grade IV articular cartilage lesion of more than 4 cm2 in the medial compartment of the knee. All patients underwent second-look arthroscopy during hardware removal. Cartilage regeneration was evaluated macroscopically using the ICRS grading system in second-look arthroscopy. We also assessed the effects of patient characteristics, such as trochlear lesions, age, and lesion size, using patient medical records. A total of 125 patients were included in the study, with an average age of 58.3 ± 6.8 years (range: 43-74 years old); 95 (76%) were female and 30 (24%) were male. The average hip-knee-ankle (HKA) angle for measuring varus deformity was 7.6° ± 2.4° (range: 5.0-14.2°). In second-look arthroscopy, the status of medial femoral condyle (MFC) cartilage was as follows: 73 (58.4%) patients with ICRS grade I, 37 (29.6%) with ICRS grade II, and 15 (12%) with ICRS grade III. No patients were staged with ICRS grade IV. Additionally, the scores [except International Knee Documentation Committee (IKDC) at 1 year] of the ICRS grade I group improved more significantly than those of the ICRS grade II and III groups. Implantation of hUCB-MSCs with concomitant HTO is an effective treatment for patients with medial compartment osteoarthritis and varus deformity. Regeneration of cartilage improves the clinical outcomes for the patients.

Allogeneic ADSCs Induce the Production of Alloreactive Memory-CD8 T Cells through HLA-ABC Antigens.

We investigated the immunogenicity of allogeneic human adipose-derived mesenchymal stem cells (ADSCs) through the production of alloreactive-CD8 T and -memory CD8 T cells, based on their human leukocyte antigen (HLA) expression. In surface antigen analysis, ADSCs do not express co-stimulatory molecules, but expresses HLA-ABC, which is further increased by exposure to the pro-inflammatory cytokines as well as IFN-γ alone. For immunogenicity analysis, allogeneic ADSCs cultured in xenofree medium (XF-ADSCs) were incubated with the recipient immune cells for allogeneic–antigen stimulation. As a result, XF-ADSCs induced IFN-γ and IL-17A release by alloreactive-CD8 T cells and the production of alloreactive-CD8 T cell through a direct pathway, although they have immunomodulatory activity. In the analysis of alloreactive memory CD8 T cells, XF-ADSCs also significantly induced the production of CFSE-low-CD8 TEM and -CD8 TCM cells. However, HLA-blocking antibodies significantly inhibited the production of CFSE-low memory-CD8 T cells, indicating that HLAs are the main antigens responsible for the development of allogeneic ADSCs’ immunogenicity. These results suggested that HLA surface antigens expressed in allogeneic MSCs should be solved in order to address concerns related to the immunogenicity problem.

Comparison of Bone Marrow Aspirate Concentrate and Allogeneic Human Umbilical Cord Blood-derived Mesenchymal Stem Cells in Patients with Kissing Lesion on Initial Arthrocopy After High Tibial Osteotomy in Medial Unicompartmental Osteoarthritis of Knee

Purpose:The purpose of this study was to compare the outcome of cartilage regeneration between bone marrow aspirate concentrate (BMAC) augmentation and the stem cell-based medicinal product (a composite of culture-expanded allogeneic hUCB-MSCs and hyaluronic acid hydrogel [Cartistem]) in medial unicompartmental osteoarthritis of kneeMethods:Out of 81 cases underwent for second look arthroscopy who treated for medial unicompartmental osteoarthritis between 2016 and 2019, 31 cases were kissing lesion which was shown full thickness cartilage defect(over ICRS grade 3B) in medial femoral cartilage and medial tibial cartilage at initial surgery. We retrospectively compared clinical outcomes, including International Knee Documentation Committee (IKDC) subjective score, Knee Society Score (KSS) pain and function, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score between BMAC group comprising of 25 cases and Cartistem group comprising of 14 cases at minimum of 1 year follow up. Also, cartilage regeneration was graded by International Cartilage Repair Society Cartilage Repair Assessment (ICRS CRA) grading system at secondary arthroscopy. Radiologic measurement including Hip-Knee-Ankle (HKA) angle, posterior tibial slope angle, and correction angle were assessed.Results:At the final follow-up, clinical outcomes were improved. However, there were no statistical significances between two groups in clinical outcome and radiologic outcome(p>0.05). Regarding the findings of second-look arthroscopy, Cartistem group was significantly better than BMAC group in medial femoral cartilage and medial tibial cartilage(p=0.002, 0.000). About medial femoral cartilage, grade I cartilage regeneration was found in 0 case, grade II in 10 cases (40%), grade III in 6 cases (16%), grade IV in 9 cases (36%) in BMAC group and grade I cartilage regeneration was found in 1 case (7.1%), grade II in 11 cases (85.7%), and grade III in 1 case (7.1%) in Cartistem group. About medial tibial cartilage, grade I cartilage regeneration was found in 0 case , grade II in 8 cases (32%), grade III in 4 cases (16%), grade IV in 13 cases (52%) in BMAC group and grade I cartilage regeneration was found in 0 case, grade II in 12 cases (85.7%), and grade III in 1 case(7.1%), grade IV in 1 case (7.1%) in cartistem group.Conclusion:Clinical outcomes were improved regardless of which augmentation was administered. However, microfracture with Cartistem is more effective for cartilage regeneration than microfracture with BMAC in medial unicompartmental OA. Keywords : High tibial osteotomy, Unicompartmental osteoarthritis, Microfracture, Cartilage regeneration, Bone marrow aspirate concentrate, Cartistem.

Allogeneic human umbilical cord-derived mesenchymal stem cells for severe bronchopulmonary dysplasia in children: study protocol for a randomized controlled trial (MSC-BPD trial)

BackgroundBronchopulmonary dysplasia (BPD) is a complex lung pathological lesion secondary to multiple factors and one of the most common chronic lung diseases. It has a poor prognosis, especially in preterm infants. However, effective therapies for this disease are lacking. Stem-cell therapy is a promising way to improve lung injury and abnormal alveolarization, and the human umbilical cord (hUC) is a good source of mesenchymal stem cells (MSCs), which have demonstrated efficacy in other diseases. We hypothesized that intravenously administered allogeneic hUC-MSCs are safe and effective for severe BPD.MethodsThe MSC-BPD trial is a randomized, single-center, open-label, dose-escalation, phase-II trial designed to investigate the safety and efficacy of hUC-MSCs in children with severe BPD. In this study, 72 patients will be enrolled and randomly divided into two intervention groups and one control group. Patients in the intervention groups will receive a low dose of hUC-MSCs (n = 24; 2.5 million cells/kg) or a high dose of hUC-MSCs (n = 24; 5 million cells/kg) in combination with traditional supportive treatments for BPD. The patients in the control group (n = 24) will be treated with traditional supportive treatments alone without hUC-MSCs. The primary outcome measures will be cumulative duration of oxygen therapy. Follow-up assessments will be performed at 1, 3, 6, 12, and 24 months post intervention, and the key outcome during follow-up will be changes on chest radiography. Statistical analyses will evaluate the efficacy of the hUC-MSC treatment.DiscussionThis will be the first randomized controlled trial to evaluate the safety and efficacy of intravenously administered hUC-MSCs in children with severe BPD. Its results should provide a new evidence-based therapy for severe BPD.Trial registrationClinicalTrials.gov, ID: NCT03601416. Registered on 26 July 2018.