Allogeneic Bone Marrow-derived Mesenchymal Stem Research Articles

Renewable Therapy Potential of Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells for Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a rare chronic respiratory disease characterized by progressive fibrotic changes in lung tissue of unknown origin, resulting in severe decline in lung function and poor prognosis with a median survival of 3 to 5 years. Current pharmacological therapies, including nintedanib and pirfenidone, aim to slow disease progression but are limited by side effects and lack of efficacy in reversing established fibrosis. This literature review explores emerging therapeutic approaches for IPF using data from PubMed, Google Scholar, and ScienceDirect databases. The review highlights mesenchymal stem cell (MSC) therapy, specifically allogeneic bone marrow-derived MSCs, as a promising option. MSC therapy demonstrates superior efficacy in improving forced vital capacity (FVC) by 3.7%, surpassing the effects of nintedanib (3.3%) and pirfenidone (-4.8%), while exhibiting minimal adverse effects. The findings underscore the potential of MSC therapy as a renewable treatment option for IPF, suggesting a paradigm shift towards addressing both disease progression and lung function restoration in affected individuals.

The treatment efficacy of bone tissue engineering strategy for repairing segmental bone defects under diabetic condition.

Diabetes mellitus is a systematic disease which exert detrimental effect on bone tissue. The repair and reconstruction of bone defects in diabetic patients still remain a major clinical challenge. This study aims to investigate the potential of bone tissue engineering approach to improve bone regeneration under diabetic condition. In the present study, decalcified bone matrix (DBM) scaffolds were seeded with allogenic fetal bone marrow-derived mesenchymal stem cells (BMSCs) and cultured in osteogenic induction medium to fabricate BMSC/DBM constructs. Then the BMSC/DBM constructs were implanted in both subcutaneous pouches and large femoral bone defects in diabetic (BMSC/DBM in DM group) and non-diabetic rats (BMSC/DBM in non-DM group), cell-free DBM scaffolds were implanted in diabetic rats to serve as the control group (DBM in DM group). X-ray, micro-CT and histological analyses were carried out to evaluate the bone regenerative potential of BMSC/DBM constructs under diabetic condition. In the rat subcutaneous implantation model, quantitative micro-CT analysis demonstrated that BMSC/DBM in DM group showed impaired bone regeneration activity compared with the BMSC/DBM in non-DM group (bone volume: 46 ± 4.4mm3 vs 58.9 ± 7.15mm3, *p < 0.05). In the rat femoral defect model, X-ray examination demonstrated that bone union was delayed in BMSC/DBM in DM group compared with BMSC/DBM in non-DM group. However, quantitative micro-CT analysis showed that after 6months of implantation, there was no significant difference in bone volume and bone density between the BMSC/DBM in DM group (199 ± 63mm3 and 593 ± 65mg HA/ccm) and the BMSC/DBM in non-DM group (211 ± 39mm3 and 608 ± 53mg HA/ccm). Our data suggested that BMSC/DBM constructs could repair large bone defects in diabetic rats, but with delayed healing process compared with non-diabetic rats. Our study suggest that biomaterial sacffolds seeded with allogenic fetal BMSCs represent a promising strategy to induce and improve bone regeneration under diabetic condition.

Genetic reprogramming with stem cells regenerates glomerular epithelial podocytes in Alport syndrome.

Glomerular filtration relies on the type IV collagen (ColIV) network of the glomerular basement membrane, namely, in the triple helical molecules containing the α3, α4, and α5 chains of ColIV. Loss of function mutations in the genes encoding these chains (Col4a3, Col4a4, and Col4a5) is associated with the loss of renal function observed in Alport syndrome (AS). Precise understanding of the cellular basis for the patho-mechanism remains unknown and a specific therapy for this disease does not currently exist. Here, we generated a novel allele for the conditional deletion of Col4a3 in different glomerular cell types in mice. We found that podocytes specifically generate α3 chains in the developing glomerular basement membrane, and that its absence is sufficient to impair glomerular filtration as seen in AS. Next, we show that horizontal gene transfer, enhanced by TGFβ1 and using allogenic bone marrow-derived mesenchymal stem cells and induced pluripotent stem cells, rescues Col4a3 expression and revive kidney function in Col4a3-deficient AS mice. Our proof-of-concept study supports that horizontal gene transfer such as cell fusion enables cell-based therapy in Alport syndrome.

Bone Marrow-derived Mesenchymal Stem Cell Therapy in Retinitis Pigmentosa.

To determine the effectiveness of bone marrow-derived mesenchymal stem cell therapy on visual acuity and visual field in patients with retinitis pigmentosa. Stem cell treatment in retinitis pigmentosa provides improvement in visual acuity and visual field. Forty-seven eyes of 27 patients diagnosed with retinitis pigmentosa were included in our study. Allogeneic bone marrow-derived mesenchymal stem cells were administered by deep subtenon injection. Complete routine ophthalmological examinations, optical coherence tomography (Zeiss, Cirrus HD-OCT) measurements, and visual field (Humphrey perimetry, 30-2) tests were performed on all patients before the treatment and on the 1st, 3rd, and 6th month after treatment. The best corrected visual acuities of the patients were determined by the Snellen chart and converted to logMAR. Visual evoked potential (VEP) and electroretinogram (ERG) examinations of the patients before the treatment and on the 6th month after the treatment were performed (Metrovision) data were compared. Visual acuities were 0.74 ± 0.49 logMAR before treatment and 0.61 ± 0.46 logMAR after treatment. Visual acuity had a statistically significant increase (p < 0.001). The visual field deviation was found to be -27.16 ± 5.77 dB before treatment and -26.59 ± 5.96 dB after treatment (p = 0.005). The ganglion cell layer was 46.26 ± 12.87 μm before treatment and 52.47 ± 12.26 μm after treatment (p = 0.003). There was a significant improvement in Pattern VEP 120º P100 amplitude compared to that before the treatment (4.43 ± 2.42 μV) and that after the treatment (5.09 ± 2.86 μV) (p = 0.013). ERG latency measurements were 18.33 ± 15.39 μV before treatment and 20.87 ± 18.64 μV after treatment for scotopic 0.01 (p = 0.02). ERG latency measurements for scotopic 3.0 were 20.75 ± 26.31 μV before treatment and 23.10 ± 28.60 μV after treatment (p = 0.014). Retinitis pigmentosa is a progressive, inherited disease that can result in severe vision loss. In retinitis pigmentosa, the application of bone marrow-derived mesenchymal stem cells by deep subtenon injection has positive effects on visual function. No systemic or ophthalmic side effects were detected in the patients during the 6-month follow-up period.

Intravitreal allogeneic mesenchymal stem cells: a non-randomized phase II clinical trial for acute non-arteritic optic neuropathy

BackgroundAn effective treatment for acute non-arteritic ischemic optic neuropathy (NA-AION) has not been known or proven yet. Previous studies have suggested a neuroprotective effect of allogeneic bone marrow-derived mesenchymal stem cells. This study aims to report the results of a clinical trial on patients with acute non-arteritic optic neuropathy (NA-AION) treated with an intravitreal injection of allogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) (MSV®).MethodsWe conducted a prospective, non-randomized, clinical phase-II study (Eudra CT number 2016-003029-40; ClinicalTrials.gov Registry NCT03173638) that included 5 patients with acute unilateral NA-AION diagnosed within 2 weeks after symptom onset and who received an intravitreal injection of allogeneic BM-MSCs (0.05 ml; cell concentration: 1.5 × 106cells/mL). The patients underwent regular ophthalmological examinations and were followed for one year.ResultsIn this trial, allogeneic BM-MSCs appeared to be safe as no patients developed signs of acute nor chronic intraocular inflammation or a significant change in intraocular pressure, although an epiretinal membrane was developed in one patient. A retrolental aggregate formed shortly after the injection spontaneously disappeared within a few weeks in another phakic patient, leaving a subcapsular cataract. Visual improvement was noted in 4 patients, and amplitudes of P100 on the visually evoked potentials recordings increased in three patients. The retinal nerve fiber layer and macular ganglion cell layer thicknesses significantly decreased during the follow-up.ConclusionsBesides the development of an epiretinal membrane in one patient, the intravitreal application of allogeneic BM-MSCs appeared to be intraocularly well tolerated. Consequently, not only NA-AION but also BM-MSCs deserve more clinical investigational resources and a larger randomized multicenter trial that would provide stronger evidence both about safety and the potential therapeutic efficacy of intravitreally injected allogeneic BM-MSCs in acute NA-AION.Trial registration: Safety Assessment of Intravitreal Mesenchymal Stem Cells for Acute Non-Arteritic Anterior Ischemic Optic Neuropathy (NEUROSTEM). NCT03173638. Registered June 02, 2017 https://clinicaltrials.gov/ct2/show/NCT03173638.

Direct Injection of Ex Vivo Expanded Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells for the Treatment of Pediatric Crohn's Perianal Fistulizing Disease.

Direct Injection of Ex Vivo Expanded Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells for the Treatment of Pediatric Crohn's Perianal Fistulizing Disease.

A pumpless monolayer microfluidic device based on mesenchymal stem cell-conditioned medium promotes neonatal mouse in vitro spermatogenesis

BackgroundChildhood cancer treatment-induced gonadotoxicity causes permanent infertility/sub-infertility in nearly half of males. The current clinical and experimental approaches are limited to cryopreservation of prepubertal testicular strips and in vitro spermatogenesis which are inadequate to achieve the expanded spermatogonial stem/progenitor cells and spermatogenesis in vitro. Recently, we reported the supportive effect of bone marrow-derived mesenchymal cell co-culture which is inadequate after 14 days of culture in static conditions in prepubertal mouse testis due to lack of microvascular flow and diffusion. Therefore, we generated a novel, pumpless, single polydimethylsiloxane-layered testis-on-chip platform providing a continuous and stabilized microfluidic flow and real-time cellular paracrine contribution of allogeneic bone marrow-derived mesenchymal stem cells.MethodsWe aimed to evaluate the efficacy of this new setup in terms of self-renewal of stem/progenitor cells, spermatogenesis and structural and functional maturation of seminiferous tubules in vitro by measuring the number of undifferentiated and differentiating spermatogonia, spermatocytes, spermatids and tubular growth by histochemical, immunohistochemical, flow cytometric and chromatographic techniques.ResultsBone marrow-derived mesenchymal stem cell-based testis-on-chip platform supported the maintenance of SALL4(+) and PLZF(+) spermatogonial stem/progenitor cells, for 42 days. The new setup improved in vitro spermatogenesis in terms of c-Kit(+) differentiating spermatogonia, VASA(+) total germ cells, the meiotic cells including spermatocytes and spermatids and testicular maturation by increasing testosterone concentration and improved tubular growth for 42 days in comparison with hanging drop and non-mesenchymal stem cell control.ConclusionsFuture fertility preservation for male pediatric cancer survivors depends on the protection/expansion of spermatogonial stem/progenitor cell pool and induction of in vitro spermatogenesis. Our findings demonstrate that a novel bone marrow-derived mesenchymal stem cell-based microfluidic testis-on-chip device supporting the maintenance of stem cells and spermatogenesis in prepubertal mice in vitro. This new, cell therapy-based microfluidic platform may contribute to a safe, precision-based cell and tissue banking protocols for prepubertal fertility restoration in future.

Design and Baseline characteristic of Phase II clinical trial of allogeneic bone marrow-derived Mesenchymal Stem Cells as a disease-modifying therapy for idiopathic Parkinson’s disease (P1-11.004)

<h3>Objective:</h3> To present the design, baseline data and initial safety of subjects enrolled in an ongoing Phase II randomized, double-blind, placebo-controlled trial of mesenchymal stem cells (MSCs) as a disease-modifying therapy for idiopathic Parkinson’s disease (PD). <h3>Background:</h3> Neuroinflammation plays a vital role in the pathogenesis of PD, thus supporting the rationale for using an immunomodulatory therapy such as MSCs for restoring homeostasis to the neuronal-glial microenvironment. <h3>Design/Methods:</h3> A total of 45 subjects were enrolled and randomized to 1 of the three treatment arms. 14 patients were randomized to arm 0, 15 were assigned to arm 1, and 16 were allocated to arm 2. The study design includes 3 treatment arms: a) 2 infusions of 10 X 10 ⁶ MSC/kg and 1 placebo; b) 3 infusions of 10 X 10⁶ MSC/kg; and c) 3 infusions of placebo. All subjects have received 3 infusions at 4-month intervals and have entered a 1-year follow-up. The last subject is projected to complete the study in August 2023. <h3>Results:</h3> All treatment‐related adverse events have been mild/moderate and temporary. There were no significant changes in CBC and CMP one month after the last infusion. Only one patient had a positive transient immunogenic reaction that could be related to the treatment. All Baseline characteristics appeared similar across groups. Subjects had a mean age of 66, an average modified H&amp;Y of 2, a disease duration between 2 and 9 years, and mean total MDS-UPDRS total score of 64.9, and a mean MDS-UPDRS-III of 36.3. All patients used dopaminergic medications before baseline evaluation. <h3>Conclusions:</h3> This study is the first FDA-approved mesenchymal stem cell study for PD. Preliminary findings showed that repeated doses of intravenous infusion of allogeneic bone marrow-derived MSCs are safe and well-tolerated in PD. Efficacy and preliminary mechanism of action data will be reported in December 2023. <b>Disclosure:</b> Dr. Schiess has nothing to disclose. The institution of Prof. Ellmore has received research support from NIMH. The institution of Dr. Shahnawaz has received research support from American Parkinson Disease Association. The institution of Dr. Shahnawaz has received research support from NIH. The institution of Dr. Shahnawaz has received research support from Texas Alzheimer’s Research &amp; Care Consortium . Dr. Shahnawaz has received intellectual property interests from a discovery or technology relating to health care. Marie-Francoise Doursout has nothing to disclose. Dr. Adams has stock in Medtronic. Dr. Tharp has nothing to disclose. Dr. Suescun has nothing to disclose.

Allogenic bone marrow-derived mesenchymal stem cells and its conditioned media for repairing acute and sub-acute peripheral nerve injuries in a rabbit model

The present study evaluated healing potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) and BM-MSCs-conditioned medium (BM-MSCs-CM) for acute and subacute injuries in the rabbit peripheral nerve injury model. The regenerative capacity of MSCs was evaluated in 40 rabbits divided into eight groups, four groups each for acute and subacute injury models. BM-MSCs and BM-MSCS-CM were prepared by isolating allogenic bone marrow from the iliac crest. After inducing sciatic nerve crush injury, different treatments consisting of PBS, Laminin, BM-MSCs + laminin, and BM-MSCS-CM + laminin were used on the day of injury in the acute injury model and after ten days of crush injury in the subacute groups. The parameters studied included: pain, total neurological score, gastrocnemius muscle weight and volume ratio, histopathology of the sciatic nerve and gastrocnemius muscle, and scanning electron microscopy (SEM). Findings indicate that BM-MSCs and BM-MSCS-CM have augmented the regenerative capacity in acute and subacute injury groups with a slightly better improvement in the subacute groups than the animals in acute injury groups. Histopathology data revealed different levels of regenerative process undergoing in the nerve. Neurological observations, gastrocnemius muscle evaluation, muscle histopathology, and the SEM results depicted better healing in animals treated with BM-MSCs and BM-MSCS-CM. With this data, it could be concluded that BM-MSCs support the healing of injured peripheral nerves, and the BM-MSCS-CM does accelerate the healing of acute and subacute peripheral nerve injuries in rabbits. However, stem cell therapy may be indicated during the subacute phase for better results.

Protocol for treating lumbar spinal canal stenosis with a combination of ultrapurified, allogenic bone marrow-derived mesenchymal stem cells and in situ-forming gel: a multicentre, prospective, double-blind randomised controlled trial

IntroductionIn patients with combined lumbar spinal canal stenosis (LSCS), a herniated intervertebral disc (IVD) that compresses the dura mater and nerve roots is surgically treated with discectomy after laminoplasty. However,...

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.

Bone marrow-derived mesenchymal stem cells alleviate paclitaxel-induced mechanical allodynia in rats.

Anticancer drug paclitaxel (PTX) frequently causes painful peripheral neuropathy; however, no medication has been shown to be effective in the treatment of this debilitating side effect. We aimed to investigate the efficacy of two different doses of allogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) on PTX-induced mechanical allodynia and spinal cytokine levels and their localization to target tissues such as the spinal cord and sciatic nerve. After the development of mechanical allodynia with repeated PTX administration, two different doses of rat BM-MSCs, low or high (1 × 106 -5 × 106 ), were transplanted into rats and the evaluation continued for 30 days. Interleukin(IL)-1β, tumor necrosis factor (TNF)-α, and IL-10 levels in spinal cord samples of animals were analyzed by enzyme-linked immunosorbent assay.PTX-induced mechanical allodynia was relieved significantly 15 days after the transplantation of high-dose of BM-MSCs. Both MSCs doses were effective in alleviating allodynia, but the onset of effect was earlier with the high dose. High-dose of BM-MSCssignificantly decreased spinal IL-1β and TNF-α levels compared to the PTX group. Fluorescent dye-labeled BM-MSCs were observed much more frequently in the sciatic nerve and spinal cord samples of the high-dose BM-MSCs transplanted group than in the low-dose group animals. In conclusion, we found that the antiallodynic effects of BM-MSCs appeared earlier when high-dose of cells were administered. We think that other mechanisms may play a role in the effects of MSCs, besides localization to damaged tissues and reducing spinal inflammatory cytokine levels. We show that BM-MSCs can be a novel approach in PTX-induced mechanical allodynia.

Adult allogenic bone marrow-derived mesenchymal stem cells for the treatment of rectovaginal fistulas in the setting of Crohn's disease.

Adult allogenic bone marrow-derived mesenchymal stem cells for the treatment of rectovaginal fistulas in the setting of Crohn's disease.

Treatment of Pulmonary Sarcoidosis Using Allogenic Bone Marrow-Derived Mesenchymal Stem Cell Therapy is Safe: A Case Report

Mesenchymal stem cells have a proven potent immunomodulatory effect both in vitro and in vivo. We report a case of a 67-year-old male patient, first diagnosed with sarcoidosis in 2005, that responded well clinically and biologically to ImmunoARTTM (developed by Educell Ltd.) allogenic, HLA-incompatible, and non-related bone marrow-derived MSCs in a dose of 106/kg. The patient presented to St. Catherine Specialty Hospital in 2021 with an exacerbation of respiratory symptoms. After a clinical and radiological examination with laboratory workup, radiological findings were consistent with pulmonary sarcoidosis, while laboratory work revealed increased leucocytes at 14.2 g/L, CRP at 51.2 mg/L, and lymphocytes at 4.25 g/L. The patient was then administered intravenous application of MSCs on three occasions in the out-patient clinic. MSC doses were prepared from a young, healthy donor who agreed to donate bone marrow for allogeneic treatment and who was negative for viral markers (HBs Ag, HBc Ab, HCV Ab, HIV 1-2 Ab, TPHA, HBV NAT, HCV NAT, HIV NAT) according to EU legislation. Cells were prepared in a controlled and verified laboratory for “Hospital exemption” cell preparation in the cleanroom facility in safety cabinet class A and expressed CD105, CD 73, and CD 90 but lacked the expression of CD45 and CD34. Before the treatment, standard print and detailed verbal information were provided to patients undergoing treatment. Immediately after the informed consent form (ICF) was signed by the patient. Throughout MSC therapy, the patient showed an improvement clinically and biologically with a decrease in inflammatory parameters. Laboratory values were assessed on days 2, 5, and 7. On day 7, leucocytes were 11.2 g/L, CRP 5.1 mg/L, and lymphocytes 4.0 g/L. In the follow-up period, the patient felt subjectively better, without any side effects of the MSC therapy. Unfortunately, the patient dropped out from follow-up, therefore, the prolonged effects of this therapy were not able to be assessed. Therefore, systemic MSC therapy presents an opportunity to treat sarcoidosis that needs to be further researched.

Treatment of Pulmonary Sarcoidosis Using Allogenic Bone Marrow-Derived Mesenchymal Stem Cell Therapy is Safe: A Case Report

Treatment of Pulmonary Sarcoidosis Using Allogenic Bone Marrow-Derived Mesenchymal Stem Cell Therapy is Safe: A Case Report

Allogeneic Cell Combination Therapy Ameliorates Chronic Kidney Disease-Induced Heart Failure with Preserved Ejection Fraction.

BackgroundLeft ventricular hypertrophy and heart failure with preserved ejection fraction (HFpEF) are primary manifestations of the cardiorenal syndrome in patients with chronic kidney disease (CKD). Therapies that improve morbidity and mortality in HFpEF are lacking. Cell-based therapies promote cardiac repair in ischemic and non-ischemic cardiomyopathies. We hypothesized that cell-based therapy ameliorates CKD-induced HFpEF.Methods and ResultsYorkshire pigs (n = 26) underwent 5/6 embolization-mediated nephrectomy. CKD was confirmed by increased creatinine and decreased glomerular filtration rate (GFR). Mean arterial pressure (MAP) was not different between groups from baseline to 4 weeks. HFpEF was evident at 4 weeks by increased LV mass, relative wall thickening, end-diastolic pressure, and end-diastolic pressure-volume relationship, with no change in ejection fraction (EF). Four weeks post-embolization, allogeneic (allo) bone marrow-derived mesenchymal stem cells (MSC; 1 × 107 cells), allo-kidney-derived stem cells (KSC; 1 × 107 cells), allo-cell combination therapy (ACCT; MSC + KSC; 1:1 ratio; total = 1 × 107 cells), or placebo (Plasma-Lyte) was delivered via intra-renal artery. Eight weeks post-treatment, there was a significant increase in MAP in the placebo group (21.89 ± 6.05 mmHg) compared to the ACCT group. GFR significantly improved in the ACCT group. EF, relative wall thickness, and LV mass did not differ between groups at 12 weeks. EDPVR improved in the ACCT group, indicating decreased ventricular stiffness.ConclusionsIntra-renal artery allogeneic cell therapy was safe in a CKD swine model manifesting the characteristics of HFpEF. The beneficial effect on renal function and ventricular compliance in the ACCT group supports further research of cell therapy for cardiorenal syndrome.

Sirtuin-1 - Mediated NF-κB Pathway Modulation to Mitigate Inflammasome Signaling and Cellular Apoptosis is One of the Neuroprotective Effects of Intra-arterial Mesenchymal Stem Cell Therapy Following Ischemic Stroke.

Stroke results in long term serious disability that affect millions across the globe. Several clinical and preclinical studies have reinforced the therapeutic use of stem cells in stroke patients to enhance their quality of life. Previous studies from our lab have demonstrated that 1*105 allogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) when given intraarterially (IA) render neuroprotection by modulating the expression of inflammasomes. Sirtuins are a class of important deacylases having a significant role in cellular functioning. Sirtuin-1 (SIRT-1) is an important enzyme essential for regulating cellular metabolism, which is reduced following an ischemic episode. The present study aims to unviel the role of MSCs in regulating the brain SIRT-1 levels following stroke and the involvement of SIRT-1 in regulating inflammasome signaling to reduce cellular apoptosis towards rendering neuroprotection. 6h post-reversible middle cerebral artery occlusion (MCAo), ovariectomized Sprague Dawley (SD) rats were infused intraarterially with 1*105 MSCs. 24h after MCAo animals were examined for functional and behavioral outcomes. Brains were collected for assessing size of infarct and neuronal morphology. Molecular and immunofluroscence studies were also performed for assessing changes in gene and protein expressions. Extent of apoptosis was also determined in different groups. Inhibition study with SIRT-1 specific inhibitor EX-527 was also performed. A reduction in infarct size and improvement in motor functional and behavioral outcomes following infusion of MSCs IA at 6h post-stroke was observed. Increase in average neuronal density and neuronal length was also seen. Increased expression of SIRT-1, BDNF and concomitant reduction in the expression of different inflammatory and apoptotic markers in the brain cortical regions were observed following MSCs treatment. Our study provides a preliminary evidence that post-stroke IA MSCs therapy regulates SIRT-1 to modulate NF-κB pathway to mitigate inflammasome signaling and cellular apoptosis. This study using IA approach for administering MSCs is highly relevant clinically. Our study is the first to report that neuroprotective effects of IA MSCs in rodent focal ischemia is mediated by SIRT-1 regulation of inflammasome signaling.

Tratamiento de la laminitis crónica en equinos utilizando células troncales mesenquimales alogénicas de la médula ósea

Chronic laminitis is a disabling condition that affects the laminar corium of the horse’s hooves. Commonly, it develops as a collateral injury of numerous primary systemic diseases. It is believed that the critical physiopathological event that renders a hoof laminitic is the loss of mesenchymal stem cells. This loss greatly impairs the ability of the laminar corium to regenerate. Although previous work provides credibility to this notion, there remain unsettled issues that must be addressed before accepting it as a well-founded fact. Here, it was reexamined the central tenet of the physiopathological model of laminitis by infusing allogeneic bone marrow-derived mesenchymal stem cells (ABM-MSCs), through the digital palmar vein, into the hooves of horses afflicted by chronic laminitis. Horses were clinically monitored during 6 mo by evaluating them monthly using the lameness-modified Obel-Glasgow’s scale and hooves thermography. Venograms and lamellar biopsies were taken at the beginning and at the end of the study period to gathered evidence on vascular remodeling and laminar corium regeneration. The results showed that ABM-MSCs infusion promotes vascular remodeling and laminar corium regeneration, further supporting that the loss of stem cells is the critical event leading to chronic laminitis. This work also demonstrated that the infusion of ABM-MSCs is safe since the treated horses did not develop local or systemic, negative clinical manifestations attuned with rejection reactions, at least during the 6-mo period they were follow up and under the therapeutic scheme proposed.

Human allogeneic bone marrow-derived mesenchymal stem cell therapy for cerebellar ataxia: A case report

To date, there is no curable treatment option for non-hereditary degenerative cerebellar ataxia. Here we report the case of a patient with sporadic adult-onset ataxia (SAOA) who underwent allogeneic bone marrow-derived mesenchymal stem cell (MSC) therapy via the intrathecal route.

The Interdisciplinary Stem Cell Institute's Use of Food and Drug Administration-Expanded Access Guidelines to Provide Experimental Cell Therapy to Patients With Rare Serious Diseases.

The U.S. Food and Drug Administration (FDA) provides guidance for expanded access to experimental therapies, which in turn plays an important role in the Twenty-first Century Cures Act mandate to advance cell-based therapy. In cases of incurable diseases where there is a lack of alternative treatment options, many patients seek access to cell-based therapies for the possibility of treatment responses demonstrated in clinical trials. Here, we describe the use of the FDA’s expanded access to investigational new drug (IND) to address rare and emergency conditions that include stiff-person syndrome, spinal cord injury, traumatic brain stem injury, complex congenital heart disease, ischemic stroke, and peripheral nerve injury. We have administered both allogeneic bone marrow-derived mesenchymal stem cell (MSC) and autologous Schwann cell (SC) therapy to patients upon emergency request using Single Patient Expanded Access (SPEA) INDs approved by the FDA. In this report, we present our experience with 10 completed SPEA protocols.