Autologous Bone Marrow-derived Cells Research Articles

REGENERATE-COBRA: A phase II randomized sham-controlled trial assessing the safety and efficacy of intracoronary administration of autologous bone marrow-derived cells in patients with refractory angina

AimsThe REGENERATE-COBRA trial (NCT05711849) will assess the safety and efficacy of an intracoronary infusion of autologous bone marrow-derived mononuclear cells in refractory angina patients with no revascularization options who are symptomatic despite optimal medical and device therapy. MethodsREGENERATE-COBRA is a single site, blinded, randomized, sham-controlled, Phase II clinical trial enrolling 110 refractory angina patients with no revascularization options who are symptomatic despite optimal medical and device therapy. Patients will be randomized to either autologous bone marrow derived-mononuclear cells or a sham procedure. Patients in the cell-treated arm will undergo a bone marrow aspiration and an intracoronary infusion of autologous bone marrow derived-mononuclear cells. Patients in the control arm will undergo a sham bone marrow aspiration and a sham intracoronary infusion. The trial's primary endpoint is an improvement in Canadian Cardiovascular Society (CCS) angina class by 2 classes between baseline and 6 months. Secondary endpoints include change in: CCS class at 12 months, myocardial ischemic burden (as measured by perfusion imaging) at 6 months, quality of life at 6 and 12 months (as measured by EQ-5D-5L, EQ-5D-VAS and Seattle Angina Questionnaire), angina frequency at 6 and 12 months, total exercise time (as measured by a modified Bruce protocol) and major adverse cardiovascular events at 6 and 12 months. ConclusionsThis is the first trial to assess the safety and efficacy of an intracoronary infusion of autologous bone marrow-derived unfractionated mononuclear cells in symptomatic refractory angina patients who have exhausted conventional therapeutic options.

Treatment of non-hypertrophic pseudoarthrosis of long bones with a Tissue Engineered Product loaded with autologous bone marrow-derived Mesenchymal Stromal Cells: Results from a phase IIa, prospective, randomized, parallel, pilot clinical trial comparing to iliac crest autograft

BackgroundAtrophic pseudoarthrosis is a serious complication with an incidence of 5–10 % of bone fractures located in the diaphysis of long bones. Standard treatments involve aggressive surgical procedures and re-interventions requiring the use of autografts from the iliac crest as a source of bone-forming biological activity (Standard of Care, SoC). In this context, regenerative ex vivo expanded osteogenic cell-based medicines could be of interest. Particularly, Mesenchymal Stromal Cells (MSC) offer new prospects to promote bone tissue repair in pseudoarthrosis by providing biological activity in an osteoconductive and osteoinductive environment. MethodsWe conducted a phase IIa, prospective, randomised, parallel, two-arms, open-label with blinded assessor pilot clinical trial to compare SoC vs. a tissue-engineered product (TEP), composed of autologous bone marrow (BM)-derived MSCs loaded onto allogeneic decellularised, lyophilised spongy bone cubes, in a cohort of 20 patients with non-hypertrophic pseudoarthrosis of long bones. Patients were followed up for 12 months. Radiological bone healing was evaluated by standard X-ray and computed tomography (CT) scanning. Quality of life was measured using the EUROQOL-5D questionnaire. ResultsTen patients were randomized to TEP and 10 to SoC with iliac crest autograft. Manufacturing of TEP was feasible and reproducibly achieved. TEP implantation in the bone defect was successful in all cases and none of the 36 adverse events (AE) reported were related to the treatment. Efficacy analyses were performed in the Full Analysis Set (FAS) population, which included 17 patients after 3 patients withdrew from the study. The degree of consolidation, estimated by measuring Hounsfield units (HU) on CT, showed no significant differences between the two treatment groups at 12 months post treatment (main efficacy variable) (p = 0.4835) or at 6 months. ConclusionsAlthough only a small number of patients were included in our study, it is notable that no significant differences were observed between the experimental treatment and SoC, thus suggesting TEP as an alternative where autograft is not available or contraindicated.

Intravenous Autologous Bone Marrow-derived Mesenchymal Stromal Cells Delay Acute Respiratory Distress Syndrome in Swine.

Rationale: Early post injury mitigation strategies in ARDS are in short supply. Treatments with allogeneic stromal cells are administered after ARDS develops, require specialized expertise and equipment, and to date have shown limited benefit. Objectives: Assess the efficacy of immediate post injury intravenous administration of autologous or allogeneic bone marrow-derived mesenchymal stromal cells (MSCs) for the treatment of acute respiratory distress syndrome (ARDS) due to smoke inhalation and burns. Methods: Yorkshire swine (n = 32, 44.3 ± 0.5 kg) underwent intravenous anesthesia, placement of lines, severe smoke inhalation, and 40% total body surface area flame burns, followed by 72 hours of around-the-clock ICU care. Mechanical ventilation, fluids, pressors, bronchoscopic cast removal, daily lung computed tomography scans, and arterial blood assays were performed. After injury and 24 and 48 hours later, animals were randomized to receive autologous concentrated bone marrow aspirate (n = 10; 3 × 106 white blood cells and a mean of 56.6 × 106 platelets per dose), allogeneic MSCs (n = 10; 6.1 × 106 MSCs per dose) harvested from healthy donor swine, or no treatment in injured control animals (n = 12). Measurements and Main Results: The intravenous administration of MSCs after injury and at 24 and 48 hours delayed the onset of ARDS in swine treated with autologous MSCs (48 ± 10 h) versus control animals (14 ± 2 h) (P = 0.004), reduced ARDS severity at 24 (P < 0.001) and 48 (P = 0.003) hours, and demonstrated visibly diminished consolidation on computed tomography (not significant). Mortality at 72 hours was 1 in 10 (10%) in the autologous group, 5 in 10 (50%) in the allogeneic group, and 6 in 12 (50%) in injured control animals (not significant). Both autologous and allogeneic MSCs suppressed systemic concentrations of TNF-α (tumor necrosis factor-α). Conclusions: The intravenous administration of three doses of freshly processed autologous bone marrow-derived MSCs delays ARDS development and reduces its severity in swine. Bedside retrieval and administration of autologous MSCs in swine is feasible and may be a viable injury mitigation strategy for ARDS.

Intravenous transplantation of bone marrow-derived mesenchymal stromal cells in patients with multiple sclerosis, a phase I/IIa, double blind, randomized controlled study.

Multiple sclerosis (MS) is a progressive, demyelinating neurodegenerative disease of the central nervous system. MS is immune-mediated and leads to disability especially in young adults. Even though 18 MS therapy drugs were approved, they slightly inhibit disease progression and do not induce regeneration and repair in the nervous system. Mesenchymal stromal cells (MSCs) have emerged as a new therapeutic modality in regenerative medicine and tissue engineering due to their immunomodulation and bio regenerative properties. We have designed a randomized, controlled clinical trial to assess safety and possible efficacy of MSC application in MS patients. Twenty-one MS patients were enrolled. Patients were allocated in two distinct groups: treatment group, which received systemic transplantation of autologous bone marrow-derived MSCs, and control group, which received placebo at the first injections. Patients in control group received MSCs at the second injection while the treatment group received placebo. All the patients were followed for 18 months. Follow-ups included regular visits, laboratory evaluation, and imaging analysis. Control patients received MSCs six month after treatment group. No severe immediate or late adverse events were observed in both groups after interventions. We did not find any significant differences in the rate of relapses, Expanded Disability Status Scale (EDSS) score, cognitive condition, Magnetic Resonance Imaging (MRI) findings, or any biomarkers of cerebrospinal fluid between the two groups and in each group before and after cell infusion. Transplantation of autologous bone marrow-derived mesenchymal stromal cells is safe and feasible. The efficacy of transplantation of these cells should be evaluated through designing randomized clinical trials with larger sample sizes, different administration routes, other cell types (allogeneic adipose derived MSCs, allogeneic Wharton's jelly derived MSCs …), repeated injections, and longer follow-up periods.

Additional improvement in regional myocardial ischemia after intracardiac injection of bone marrow cells during CABG surgery.

Post-procedure residual ischemia is associated with worse prognosis in patients with coronary artery diasease (CAD). We evaluated whether autologous bone marrow-derived cells (BMC) contribute to additional reduction in regional stress-induced myocardial ischemia (SIMI) in patients undergoing incomplete coronary artery bypass graft surgery (CABG). In a double-blind, randomized, placebo-controlled trial, we enrolled 143 patients (82% men, 58 ± 11 years) with stable CAD and not candidates for complete CABG. They received 100 million BMC (n = 77) or placebo (n = 66) injected into ischemic non-revascularized segments during CABG. The primary outcome was improvement on SIMI quantified as the area at risk in injected segments assessed by cardiovascular magnetic resonance (CMR) 1, 6, and 12 months after CABG. The reduction in global SIMI after CABG was comparable (p = 0.491) in both groups indicating sustained beneficial effects of the surgical procedure over 12 month period. In contrast, we observed additional improvement in regional SIMI in BMC treated group (p = 0.047). Baseline regional SIMI values were comparable [18.5 (16.2-21.0) vs. 18.5 (16.5-20.7)] and reached the lowest values at 1 month [9.74 (8.25; 11.49) vs. 12.69 (10.84; 14.85)] for BMC and placebo groups, respectively. The ischemia's improvement from baseline represented a 50% difference in regional SIMI in favor of the BMC transplanted group at 30 days. We found no differences in clinical and LVEF% between groups during the 12 month follow-up period. The 1 month rate of major adverse cerebral and cardiovascular events (MACCE) (p = 0.34) and all-cause mortality (p = 0.08) did not differ between groups 1 month post intervention. We provided evidence that BMC leads to additional reduction in regional SIMI in chronic ischemic patients when injected in segments not subjected to direct surgical revascularization. This adjuvant therapy deserves further assessment in patients with advanced CAD especially in those with microcirculation dysfunction. https://clinicaltrials.gov/, identifier NCT01727063.

Autologous bone marrow-derived nucleated cell (aBMNC) transplantation improves endometrial function in patients with refractory Asherman's syndrome or with thin and dysfunctional endometrium.

The purpose was to evaluate the effect of intrauterine injection of aBMNC on the endometrial function in patients with refractory Asherman's syndrome (AS) and/or thin and dysfunctional endometrium (TE). This is a prospective, experimental, non-controlled study MATERIAL AND METHODS: The study was carried out between December 2018 and December 2020 on 20 patients, who were of age < 45 years and had oligo/amenorrhea and primary infertility due to refractory AS and/or TE. One hundred ml BM was extracted. aBMNC cells were separated according to generic volume reduction protocol by using the Cell Separation System SEPAX S-100 table top centrifuge system. We have evaluated CD34+, mononuclear cell (MNC), and total nucleated cell (TNC) counts. The transplantation aBMNC was performed by two intrauterine injections at an interval of one week, transvaginally into the endometrial-myometrial junction by an ovum aspiration needle. Midcyclic endometrial thickness (ET) and gestations after transplantation were evaluated. The mean TNC, MNC, and CD34+ cells were 11.55 ± 4.7 × 108, 3.85 ± 2.01 × 108, and 7.00 ± 2.88 × 106 at first injection, respectively, and 6.85 ± 2.67 × 108, 2.04 ± 1.11 × 108, and 3.44 ± 1.31 × 106 at second injection, respectively. The maximum posttransplantation ET was significantly higher than the maximum pretransplantation ET: 2.97 ± 0.48 vs. 5.76 ± 1.19 (mean ± standard deviation, p < 0.01). Twelve patients had frozen-thaw embryo transfers after the study. In 42% (n = 5 of 12) of the patients, pregnancy was achieved. One of the five patients delivered a healthy baby at term. Autologous BMNC transplantation may contribute to endometrial function in patients with AS and/or TE.

Left Atrial Structural and Functional Response in Kidney Transplant Recipients Treated With Mesenchymal Stromal Cell Therapy and Early Tacrolimus Withdrawal

Autologous bone marrow-derived mesenchymal stromal cell (MSC) therapy and withdrawal of calcineurin inhibitors (CNIs) has been shown to improve systemic blood pressure control and left ventricular hypertrophy regression in kidney transplant recipients. In the current subanalysis, we aimed to evaluate the impact of this novel immunosuppressive regimen on the longitudinal changes of left atrial (LA) structure and function after kidney transplantation. Kidney transplant recipients randomized to MSC therapy-infused at weeks 6 and 7 after transplantation, with complete discontinuation at week 8 of tacrolimus (MSC group)-or standard tacrolimus dose (control group) were evaluated with transthoracic echocardiography at weeks 4 and 24 after kidney transplantation. The changes in echocardiographic parameters were compared between the randomization arms using an analysis of covariance model adjusted for baseline variable. Fifty-four participants (MSC therapy=27; tacrolimus therapy=27) were included. There was no significant interaction between the allocated treatment and the changes of indexed maximal LA volume (LAVImax) over the study period. Conversely, between 4 and 24weeks post-transplantation, an increase in indexed minimal LA volume (LAVImin) was observed in control subjects, while it remained unchanged in the MSC group, leading to a significant difference between groups (P=.021). Additionally, patients treated with MSC therapy showed a benefit in LA function, assessed by a significant interaction between changes in LA emptying fraction and LA reservoir strain and the randomization arm (P=.012 and P=.027, respectively). The combination of MSC therapy and CNIs withdrawal prevents progressive LA dilation and dysfunction in the first 6months after kidney transplantation. LAVImin and LA reservoir strain may be more sensitive markers of LA reverse remodeling, compared with LAVImax.

Repeat infusion of autologous bone marrow cells in progressive multiple sclerosis – A phase I extension study (SIAMMS II)

BackgroundDuring the safety and feasibility ‘Study of Intravenous Autologous Marrow in Multiple Sclerosis (SIAMMS)’, intravenous infusion of autologous marrow was well tolerated. The efficacy of the approach is being explored in a placebo-controlled randomised controlled trial (ACTiMuS, NCT01815632) but it is not known whether repeated infusions will be required to optimise benefit. The objective of the current study was to explore the safety and feasibility of repeat treatment with intravenous autologous bone marrow for patients with progressive multiple sclerosis (MS). Methods‘SIAMMS II’ was a prospective, single centre phase I extension study in which participants in the SIAMMS study were offered repeat bone marrow harvest and infusion of autologous, unfractionated bone marrow as a day-case procedure. The primary outcome measure was number of adverse events and secondary outcome measures included change in clinical rating scales of disability, global evoked potential and cranial magnetic resonance imaging (MRI). ResultsIn total, 4 of the 6 participants in the SIAMMS study had repeat bone marrow harvest and infusion of filtered autologous marrow as a day case procedure which was well tolerated. There were no serious adverse effects. Additional outcome measures including clinical scales, global evoked potentials and cranial MRI were stable. ConclusionSIAMMS II demonstrates the safety and feasibility of repeated, non-myeloablative autologous bone marrow-derived cell therapy in progressive MS.

Five-year follow-up of intracoronary autologous cell therapy in acute myocardial infarction: the REGENERATE-AMI trial.

AimsThe long‐term outcomes of the intracoronary delivery of autologous bone marrow‐derived cells (BMCs) after acute myocardial infarction are not well established. Following the promising 1 year results of the REGENERATE‐AMI trial (despite it not achieving its primary endpoint), this paper presents the analysis of the 5 year clinical outcomes of these acute myocardial infarction patients who were treated with an early intracoronary autologous BMC infusion or placebo.Methods and resultsA 5 year follow‐up of major adverse cardiac events (defined as the composite of all‐cause death, recurrent myocardial infarction, and all coronary revascularization) and of rehospitalization for heart failure was completed in 85 patients (BMC n = 46 and placebo n = 39). The incidence of major adverse cardiac events was similar between the BMC‐treated patients and the placebo group (26.1% vs. 18.0%, P = 0.41). There were no cases of cardiac death in either group, but an increase in non‐cardiac death was seen in the BMC group (6.5% vs. 0%, P = 0.11). The rates of recurrent myocardial infarction and repeat revascularization were similar between the two groups. There were no cases of rehospitalization for heart failure in either group.ConclusionThis 5 year follow‐up analysis of the REGENERATE‐AMI trial did not show an improvement in clinical outcomes for patients treated with cell therapy. This contrasts with the 1 year results which showed improvements in the surrogate outcome measures of ejection fraction and myocardial salvage index.

The Efficacy and Safety of Intrathecal Autologous Bone Marrow-Derived Mesenchymal Stromal Cells in Amyotrophic Lateral Sclerosis: A Pilot Study.

Purpose: Amyotrophic lateral sclerosis (ALS) is an uncommon and aggressive neurodegenerative disorder that influences the lower and upper motor neurons. There are low eligible drugs for ALS treatment; in this regard, supplemental and replacement treatments are essential. There are relative studies in the field of mesenchymal stromal cells (MSCs) therapy in ALS, but the different methods, differently used medium, and difference in follow-up periods affect the outcome treatment. Methods: The current survey is a single-center, phase I clinical trial to evaluating the efficacy and safety of autologous bone marrow (BM)-derived MSCs through intrathecal administration in ALS patients. MNCs were isolated from BM specimens and cultured. The clinical outcome was evaluated based Revised Amyotrophic Lateral Sclerosis Functional Rating (ALSFRS-R) Scale. Results: Each patient received 15±3×106 cells through subarachnoid space. No adverse events (AEs) were detected. Just one patient experienced a mild headache after injection. Following injection, no new intradural cerebrospinal pathology transplant-related was observed. None of the patients' pathologic disruptions following transplantation were detected by magnetic resonance imaging (MRI). The additional analyses have shown the average rate of ALSFRS-R score and forced vital capacity (FVC) reduction have decreased during 10 months following MSCs transplantation versus the pretreatment period, from -5.4±2.3 to -2±3.08 ALSFRS-R points/period (P=0.014) and -12.6±5.22% to -4.8±14.72%/period (P<0.001), respectively. Conclusion: These results have shown that autologous MSCs transplantation reduces the disease's progression and has favorable safety. Trial Registration: This study performed as a phase I clinical trial (code IRCT20200828048551N1).

Cardiovascular Effects of Autologous Bone Marrow-Derived Mesenchymal Stromal Cell Therapy With Early Tacrolimus Withdrawal in Renal Transplant Recipients: An Analysis of the Randomized TRITON Study.

BackgroundAfter renal transplantation, there is a need of immunosuppressive regimens that effectively prevent allograft rejection while minimizing cardiovascular complications. This substudy of the TRITON trial evaluated the cardiovascular effects of autologous bone marrow–derived mesenchymal stromal cells (MSCs) in renal transplant recipients.Methods and ResultsRenal transplant recipients were randomized to MSC therapy, infused at weeks 6 and 7 after transplantation, with withdrawal at week 8 of tacrolimus or standard tacrolimus dose. Fifty‐four patients (MSC group=27; control group=27) underwent transthoracic echocardiography at weeks 4 and 24 after transplantation and were included in this substudy. Changes in clinical and echocardiographic variables were compared. The MSC group showed a benefit in blood pressure control, assessed by a significant interaction between changes in diastolic blood pressure and the treatment group (P=0.005), and a higher proportion of patients achieving the predefined blood pressure target of <140/90 mm Hg compared with the control group (59.3% versus 29.6%, P=0.03). A significant reduction in left ventricular mass index was observed in the MSC group, whereas there were no changes in the control group (P=0.002). The proportion of patients with left ventricular hypertrophy decreased at 24 weeks in the MSC group (33.3% versus 70.4%, P=0.006), whereas no changes were noted in the control group (63.0% versus 48.1%, P=0.29). Additionally, MSC therapy prevented progressive left ventricular diastolic dysfunction, as demonstrated by changes in mitral deceleration time and tricuspid regurgitant jet velocity.ConclusionsMSC strategy is associated with improved blood pressure control, regression of left ventricular hypertrophy, and prevention of progressive diastolic dysfunction at 24 weeks after transplantation.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT03398681.

The relationship between myeloid-derived supressor cells and clinico-laboratory parameters in patients with liver cyrrosis

In the present study, we used multicolor flow cytometry assay to measure the numbers of various myeloid suppressor cell subpopulations (Lin-HLA-DR-CD33+, Lin-HLA-DR-CD33+CD66b+, and CD14+HLA-DRlow/-) in peripheral blood of 51 participants, including 33 patients with viral- and 1 8 patients with «nonviral» (alcoholic or biliary/autoimmune) liver cirrhosis. Patients in both groups had increased proportions of Lin-HLA-DR-CD33+, Lin-HLA-DR-CD33+CD66b+, and CD 14+HLA-DRlow/-cells which levels did not depend on the type and replication of the virus in viral liver cirrhosis. In viral liver cirrhosis, the relative numbers of Lin-HLA-DR-CD33+cells directly correlated with the albumin levels (Rs=0.45; p=0.029). In «nonviral» group an inverse relationship was found between these indicators (Rs = -0.56; p=0.02), in addition the proportion of Lin-HLA-DR-CD33+and CD14+HLA-DRlow/-cells directly correlated with disease severity scores (Child-Pugh and MELD) direct correlation of the proportion of Lin-HLA-DR-CD33+and CD14+HLA-DRlow/-cells with the disease severity scores (Child-Pugh and MELD). Comparison of the initial content of myeloid suppressors with the response to complex therapy (that included autologous bone marrow-derived cell transplantation), showed that in viral liver cirrhosis, the proportion of Lin-HLA-DR-CD33+cells was characterized by a prognostic significance and, at values

Reduced expression of mitochondrial fumarate hydratase in progressive multiple sclerosis contributes to impaired in vitro mesenchymal stromal cell-mediated neuroprotection

Background: Cell-based therapies for multiple sclerosis (MS), including those employing autologous bone marrow-derived mesenchymal stromal cells (MSC) are being examined in clinical trials. However, recent studies have identified abnormalities in the MS bone marrow microenvironment. Objective: We aimed to compare the secretome of MSC isolated from control subjects (C-MSC) and people with MS (MS-MSC) and explore the functional relevance of findings. Methods: We employed high throughput proteomic analysis, enzyme-linked immunosorbent assays and immunoblotting, as well as in vitro assays of enzyme activity and neuroprotection. Results: We demonstrated that, in progressive MS, the MSC secretome has lower levels of mitochondrial fumarate hydratase (mFH). Exogenous mFH restores the in vitro neuroprotective potential of MS-MSC. Furthermore, MS-MSC expresses reduced levels of fumarate hydratase (FH) with downstream reduction in expression of master regulators of oxidative stress. Conclusions: Our findings are further evidence of dysregulation of the bone marrow microenvironment in progressive MS with respect to anti-oxidative capacity and immunoregulatory potential. Given the clinical utility of the fumaric acid ester dimethyl fumarate in relapsing–remitting MS, our findings have potential implication for understanding MS pathophysiology and personalised therapeutic intervention.

Contemporary Outcomes of Distal Lower Extremity Bypass for Chronic Limb-Threatening Ischemia and A Model-Based Comparison With Autologous Bone Marrow-Derived Cell Therapy for Limb Preservation

The standard of therapy for chronic limb-threatening ischemia (CLTI) is revascularization. However, for patients for whom below-the-knee bypass is indicated, an autologous great saphenous vein (GSV), the optimal conduit, might not be available. For these patients, an alternative conduit, such as a synthetic or cryopreserved biologic graft, will be necessary. Contemporary outcomes of distal bypass with these suboptimal conduits have not been well described, and recent advances in novel nonoperative management such as autologous bone marrow cell (BMC) therapy warrant a comparative analysis as a potential alternative for limb preservation.

Safety of Intravenous Autologous Bone Marrow-Derived Mesenchymal Cell Transplantation in 5 Patients With Reduced Left Ventricular Ejection Fraction.

Background: Although intracardiac injection or intracoronary delivery of mesenchymal stem cells (MSCs) has been reported, there have been few studies on the intravenous injection of MSCs, particularly in Japan.Methods and Results: Five patients with left ventricular ejection fraction (LVEF) ≤45% received 1.0×108 MSCs intravenously. The procedure did not induce significant changes in vital signs. One patient had an elevated body temperature after 1 day, but recovered spontaneously. Laboratory tests remained normal for 1 month after cell delivery. Computed tomography was performed after 1–2 years, and there was no evidence of malignancy.Conclusions: In this pilot study of patients with reduced LVEF, intravenous MSC delivery had no adverse effects.

Autologous bone marrow-derived mesenchymal stromal cell therapy with early tacrolimus withdrawal: The randomized prospective, single-center, open-label TRITON study

After renal transplantation, there is a need for immunosuppressive regimens which effectively prevent allograft rejection, while preserving renal function and minimizing side effects. From this perspective, mesenchymal stromal cell (MSC) therapy is of interest. In this randomized prospective, single‐center, open‐label trial, we compared MSCs infused 6 and 7 weeks after renal transplantation and early tacrolimus withdrawal with a control tacrolimus group. Primary end point was quantitative evaluation of interstitial fibrosis in protocol biopsies at 4 and 24 weeks posttransplant. Secondary end points included acute rejection, graft loss, death, renal function, adverse events, and immunological responses. Seventy patients were randomly assigned of which 57 patients were included in the final analysis (29 MSC; 28 controls). Quantitative progression of fibrosis failed to show benefit in the MSC group and GFR remained stable in both groups. One acute rejection was documented (MSC group), while subclinical rejection in week 24 protocol biopsies occurred in seven patients (four MSC; three controls). In the MSC group, regulatory T cell numbers were significantly higher compared to controls (p = .014, week 24). In conclusion, early tacrolimus withdrawal with MSC therapy was safe and feasible without increased rejection and with preserved renal function. MSC therapy is a potentially useful approach after renal transplantation.

Ten-year results of mesenchymal stromal cell transplantation augmented with vascularised bone grafts for advanced osteonecrosis of the femoral head

BackgroundA prospective, open-label clinical trial, in which transplantation of cultured autologous bone marrow-derived multipotent mesenchymal stromal cells in combination with vascularised bone grafts for the treatment of post-collapse extensive osteonecrosis of the femoral head in ten patients, was conducted previously. The aim of this study was to assess the 10-year clinical and radiographic results of that study. MethodsPatients were evaluated for radiographic progression of osteonecrosis of the femoral head using anteroposterior radiographs at 10 years postoperatively. Clinical score and hip function, including the timed up and go test, were also estimated. ResultsOsteoarthritic changes in the affected hip were found in five of the ten patients, two of whom had undergone total hip arthroplasty at 7 and 9 years postoperatively. Five of the six cases (83.3%) in which pre-operative femoral head collapse was less than 3 mm, had no further collapse. On the other hand, all four cases in which pre-operative femoral head collapse was ≥3 mm, showed osteoarthritic changes within 10 years. The average clinical score significantly improved postoperatively and was maintained at 10 years. ConclusionsConsidering that eight of 10 post-collapse cases could avoid total hip arthroplasty conversion with good clinical results for 10 years and five of 6 post-collapse cases (collapse <3 mm) could avoid further collapse and osteoarthritic changes for 10 years, mesenchymal stromal cell transplantation in combination with vascularised bone grafts could be an effective treatment for post-collapse osteonecrosis of the femoral head.

Long-Term Effects of Adjuvant Intravitreal Treatment with Autologous Bone Marrow-Derived Lineage-Negative Cells in Retinitis Pigmentosa.

Background Autologous bone marrow-derived lineage-negative (Lin−) cells present antiapoptotic and neuroprotective activity. The aim of the study was to evaluate the safety and efficacy of novel autologous Lin− cell therapy during a 12-month follow-up period. Methods Intravitreal injection of Lin− cells in 30 eyes with retinitis pigmentosa (RP) was performed. The fellow eyes (FEs) were considered control eyes. Functional and morphological eye examinations were performed before and 1, 3, 6, 9, and 12 months after the injection. Results Patients whose symptoms started less than 10 years ago gained 14 ± 10 letters, while those with a longer disease duration gained 2.86 ± 8.54 letters compared to baseline at the 12-month follow-up (p = 0.021). There were significantly higher differences in response densities of P1-wave amplitudes in the first ring of multifocal ERGs in treated eyes than FE recordings in all follow-up points were detected. Accordingly, the mean deviation in 10-2 static perimetry improved significantly in the treated eyes compared with fellow eyes 12 months after the procedure. The QoL scores improved significantly and lasted until the 9-month visit. Conclusion Lin− cell-based therapy is safe and effective, especially for a well-selected group of RP patients who still maintained good function of the foveal cones.

Local administration of allogeneic or autologous bone marrow-derived mesenchymal stromal cells enhances bone formation similarly in distraction osteogenesis

Background aimsDistraction osteogenesis (DO) is a surgical technique to promote bone regeneration that requires a long time for bone healing. Bone marrow-derived mesenchymal stromal cells (MSCs) have been applied to accelerate bone formation in DO. Allogeneic MSCs are attractive, as they could be ready to use in clinics. Whether allogeneic MSCs would have an effect similar to autologous MSCs with regard to promoting bone formation in DO is still unknown. This study compares the effect of autologous MSCs versus allogeneic MSCs on bone formation in a rat DO model. MethodsRat bone marrow-derived MSCs were isolated, characterized and expanded in vitro. Adult rats were subjected to right tibia transverse osteotomy. On the third day of distraction, each rat received one injection of phosphate-buffered saline (PBS), autologous MSCs or allogeneic MSCs at the distraction site. Tibiae were harvested after 28 days of consolidation for micro-computed tomography examination, mechanical test and histological analysis. ResultsResults showed that treatment with both allogeneic and autologous MSCs promoted bone formation, with significantly higher bone mass, mechanical properties and mineral apposition rate as well as expression of angiogenic and bone formation markers at the regeneration sites compared with the PBS-treated group. No statistical difference in bone formation was found between the allogeneic and autologous MSC treatment groups. ConclusionsThis study indicates that allogeneic and autologous MSCs have a similar effect on promoting bone consolidation in DO. MSCs from an allogeneic source could be used off-the-shelf with DO to achieve early bone healing.

Retinal function after intravitreal injection of autologous bone marrow-derived mesenchymal stromal cells in advanced glaucoma

To report electroretinographic (ERG) findings in advanced glaucoma treated with a single intravitreal injection of bone marrow-derived mesenchymal stem cells (MSCs). Intravitreal injection of autologous MSCs (1 × 106 cells) was performed in 2 eyes from 2 patients with open-angle glaucoma in advanced stage of optic neuropathy (ClinicalTrials.gov, NCT02330978, 01.05.2015): cup/disk ratio worse than 0.9, visual field mean deviation index lower than -15dB, visual acuity of light perception, but controlled intraocular pressure. ERG tests were recorded at baseline and week 1, 4 and 48 after injection, using DTL electrodes following the ISCEV standard: After dark adaptation, ERG was elicited using white flashes of 0.01cd.s/m2 and 3.0cd.s/m2, followed by 10-min light adaptation (30cd/m2) and stimuli of 3.0cd.s/m2 and 30Hz flicker. Patients did not show improvement on visual acuity or visual field after treatment. At baseline, ERG responses showed typical findings for advanced glaucoma, with a- and b-wave amplitude and latency within normative range, but reduced photopic negative responses. No noteworthy changes were observed on ERG responses for both cases up to 1week after treatment, but at day 15, one patient showed retinal detachment with proliferative vitreoretinopathy and was removed from the trial. The other patient kept ERG responses stable throughout study period. Although no ERG response changes were observed after MSCs injection in one case, the complication observed on the second one, along with the lack of visual function improvement, warrants further studies involving modified MSCs to treat ocular disorders, including glaucoma. ClinicalTrials.gov, NCT02330978- missed in pdf.