Transplantation Of Bone Marrow-derived Cells Research Articles

Mesenchymal stem cell-derived small extracellular vesicles enhance the therapeutic effect of retinal progenitor cells in retinal degenerative disease rats.

Our previous study demonstrated that combined transplantation of bone marrow-derived mesenchymal stem cells and retinal progenitor cells in rats has therapeutic effects on retinal degeneration that are superior to transplantation of retinal progenitor cells alone. Bone marrow- derived mesenchymal stem cells regulate and interact with various cells in the retinal microenvironment by secreting neurotrophic factors and extracellular vesicles. Small extracellular vesicles derived from bone marrow-derived mesenchymal stem cells, which offer low immunogenicity, minimal tumorigenic risk, and ease of transportation, have been utilized in the treatment of various neurological diseases. These vesicles exhibit various activities, including anti-inflammatory actions, promotion of tissue repair, and immune regulation. Therefore, novel strategies using human retinal progenitor cells combined with BMSC-derived small extracellular vesicles may represent an innovation in stem cell therapy for retinal degeneration. In this study, we developed such an approach utilizing retinal progenitor cells combined with bone marrow-derived mesenchymal stem cell-derived small extracellular vesicles to treat retinal degeneration in Royal College of Surgeons rats, a genetic model of retinal degeneration. Our findings revealed that the combination of bone marrow-derived mesenchymal stem cell-derived small extracellular vesicles and retinal progenitor cells significantly improved visual function in these rats. The addition of bone marrow-derived mesenchymal stem cell-derived small extracellular vesicles as adjuvants to stem cell transplantation with retinal progenitor cells enhanced the survival, migration, and differentiation of the exogenous retinal progenitor cells. Concurrently, these small extracellular vesicles inhibited the activation of regional microglia, promoted the migration of transplanted retinal progenitor cells to the inner nuclear layer of the retina, and facilitated their differentiation into photoreceptors and bipolar cells. These findings suggest that bone marrow-derived mesenchymal stem cell-derived small extracellular vesicles potentiate the therapeutic efficacy of retinal progenitor cells in retinal degeneration by promoting their survival and differentiation.

Transplantation of Mesenchymal Stem Cells Derived from Old Rats Improves Healing and Biomechanical Properties of Vaginal Tissue Following Surgical Incision in Aged Rats.

Pelvic floor dysfunction encompasses a group of disorders that negatively affect the quality of women's lives. These include pelvic organ prolapse (POP), urinary incontinence, and sexual dysfunction. The greatest risk factors for prolapse are increased parity and older age, with the largest group requiring surgical intervention being post-menopausal women over 65. Prolapse recurrence rates following surgery were reported to be as high as 30%. This may be attributed to ineffective healing in the elderly. Autologous stem cell transplantation during surgery may improve surgical results. In our previous studies, we showed that the transplantation of bone marrow-derived mesenchymal stem cells (MSCs) from young donor rats improved the healing of full-thickness vaginal surgical incision in the vaginal wall of old rats, demonstrated by both histological and functional analysis. In order to translate these results into the clinical reality of autologous MSC transplantation in elderly women, we sought to study whether stem cells derived from old donor animals would provide the same effect. In this study, we demonstrate that MSC transplantation attenuated the inflammatory response, increased angiogenesis, and exhibited a time-dependent impact on MMP9 localization. Most importantly, transplantation improved the restoration of the biomechanical properties of the vagina, resulting in stronger healed vaginal tissue. These results may pave the way for further translational studies focusing on the potential clinical autologous adjuvant transplantation of MSCs for POP repair for the improvement of surgical outcomes.

Autologous bone marrow-derived mesenchymal stem cells and endothelial progenitor cells transplantation showed potential benefits for type 2 diabetes mellitus Filipino patients: a case series

Autologous bone marrow-derived mesenchymal stem cells and endothelial progenitor cells transplantation showed potential benefits for type 2 diabetes mellitus Filipino patients: a case series

Leveraging stem cells to combat hepatitis: a comprehensive review of recent studies.

Hepatitis is a significant global public health concern, with viral infections being the most common cause of liver inflammation. Antiviral medications are the primary treatments used to suppress the virus and prevent liver damage. However, the high cost of these drugs and the lack of awareness and stigma surrounding the disease create challenges in managing hepatitis. Stem cell therapy has arisen as a promising therapeutic strategy for hepatitis by virtue of its regenerative and immunomodulatory characteristics. Stem cells have the exceptional capacity to develop into numerous cell types and facilitate tissue regeneration, rendering them a highly promising therapeutic avenue for hepatitis. In animal models, stem cell therapy has demonstrated worthy results by reducing liver inflammation and improving liver function. Furthermore, clinical trials have been undertaken to assess the safety and effectiveness of stem cell therapy in individuals with hepatitis. This review aims to explore the involvement of stem cells in treating hepatitis and highlight the findings from studies conducted on both animals and humans. The objective of this review is to primarily concentrate on the ongoing and future clinical trials that assess the application of stem cell therapy in the context of hepatitis, including the transplantation of autologous bone marrow-derived stem cells, human induced pluripotent stem cells, and other mesenchymal stem cells. In addition, this review will explore the potential merits and constraints linked to stem cell therapy for hepatitis, as well as its prospective implications in the management of this disease.

Intravenous transplantation of bone marrow-derived mesenchymal stem cells improved behavioral deficits and altered fecal microbiota composition of BTBR mice

AimsIt is recognized that autism spectrum disorder (ASD) is a highly complex neurodevelopmental disorder with communication deficits as well as multiple social barriers. The core symptoms of ASD are not treatable with current therapeutics. Therefore, finding new treatment strategies for ASD is urgently needed. Mesenchymal stem cells (MSC) have been shown to be a promising therapeutic approach in previous studies. However, the underlying mechanisms of MSC treatment for ASD through gut microbiota remain unclear and require further investigation. Main methodsBTBR mice were used as ASD model and then randomly assigned to the human bone marrow-derived mesenchymal stem cell (hBMMSC) intravenous treatment group or vehicle treatment group. C57BL/6J (C57) mice served as control. Multiple social behavioral tests were performed during the 6-week period and fecal samples were collected at different time points for 16 s rRNA sequencing analysis. Key findingsThe administration of hBMMSC improved social deficits of BTBR mice in the open field test (OFT), light-dark box test (LBT), novel object recognition (NOR), and free social test (FST), while also significantly reducing stereotypic behaviors. Additionally, hBMMSC administration notably reversed the alterations of microbiota abundance in BTBR mice, particularly the Firmicutes/Bacteroidetes ratio. Several specific differential taxa were further selected and showed a correlation with the prognosis and behavioral scores of ASD. SignificanceOverall, intravenous treatment with hBMMSC had a beneficial impact on ASD by ameliorating social deficits and modifying microbiota compositions. This outcome indicates that hBMMSC intravenous transplantation could be a promising therapeutic strategy for enhancing ASD symptoms improvements.

Transplantation of bone marrow-derived mesenchymal stem cells ameliorated dopamine system impairment in a D-galactose-induced brain ageing in rats.

Ageing is the primary risk factor for Parkinson's disease. Progressive motor and coordination decline that occurs with ageing has been linked to nigrostriatal dysfunction. Few studies have investigated the efficacy of mesenchymal stem cells in ameliorating the structural and functional alterations in the ageing nigrostriatal system. This study is the first to evaluate the effects of intravenous injection of bone marrow-derived mesenchymal stem cells (BMMSCs) in a D-galactose- induced rat model of nigrostriatal ageing. BMMSCs were intravenously injected once every 2 weeks for 8 weeks. The transplanted cells survived, migrated to the brain, and differentiated into dopaminergic neurones and astrocytes. BMMSC transplantation improved locomotor activity, restored dopaminergic system function, preserved atrophic dopaminergic neurones in the substantia nigra, exerted antioxidative effects, and restored neurotrophic factors. Our findings demonstrate the efficacy of BMMSC injection in a nigrostriatal ageing rat model, and suggest that these cells may provide an effective therapeutic approach for the ageing nigrostriatal system.

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.

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.

Binucleated human bone marrow-derived mesenchymal cells can be formed during neural-like differentiation with independence of any cell fusion events

Although it has been reported that bone marrow-derived cells (BMDCs) can transdifferentiate into neural cells, the findings are considered unlikely. It has been argued that the rapid neural transdifferentiation of BMDCs reported in culture studies is actually due to cytotoxic changes induced by the media. While transplantation studies indicated that BMDCs can form new neurons, it remains unclear whether the underlying mechanism is transdifferentiation or BMDCs-derived cell fusion with the existing neuronal cells. Cell fusion has been put forward to explain the presence of gene-marked binucleated neurons after gene-marked BMDCs transplantation. In the present study, we demostrated that human BMDCs can rapidly adopt a neural-like morphology through active neurite extension and binucleated human BMDCs can form with independence of any cell fusion events. We also showed that BMDCs neural-like differentiation involves the formation of intermediate cells which can then redifferentiate into neural-like cells, redifferentiate back to the mesenchymal fate or even repeatedly switch lineages without cell division. Furthermore, we have discovered that nuclei from intermediate cells rapidly move within the cell, adopting different morphologies and even forming binucleated cells. Therefore, our results provide a stronger basis for rejecting the idea that BMDCs neural transdifferentiation is merely an artefact.

BMSCs Promote Differentiation of Enteric Neural Precursor Cells to Maintain Neuronal Homeostasis in Mice With Enteric Nerve Injury

Our previous study showed that transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) promoted functional enteric nerve regeneration in denervated mice but not through direct transdifferentiation. Homeostasis of the adult enteric nervous system (ENS) is maintained by enteric neural precursor cells (ENPCs). Whether ENPCs are a source of regenerated nerves in denervated mice remains unknown. Genetically engineered mice were used as recipients, and ENPCs were traced during enteric nerve regeneration. The mice were treated with benzalkonium chloride to establish a denervation model and then transplanted with BMSCs 3 days later. After 28 days, the gastric motility and ENS regeneration were analyzed. The interaction between BMSCs and ENPCs invitro was further assessed. Twenty-eight days after transplantation, gastric motility recovery (gastric emptying capacity, P < .01; gastric contractility, P < .01) and ENS regeneration (neurons, P < .01; glial cells, P < .001) were promoted in BMSCs transplantation groups compared with non-transplanted groups in denervated mice. More importantly, we found that ENPCs could differentiate into enteric neurons and glial cells in denervated mice after BMSCs transplantation, and the proportion of Nestin+/Ngfr+ cells differentiated into neurons was significantly higher than that of Nestin+ cells. A small number of BMSCs located in the myenteric plexus differentiated into glial cells. Invitro, glial cell-derived neurotrophic factor (GDNF) from BMSCs promotes the migration, proliferation, and differentiation of ENPCs. In the case of enteric nerve injury, ENPCs can differentiate into enteric neurons and glial cells to promote ENS repair and gastric motility recovery after BMSCs transplantation. BMSCs expressing GDNF enhance the migration, proliferation, and differentiation of ENPCs.

Leukemia Inhibitory Factor Facilitates Self-Renewal and Differentiation and Attenuates Oxidative Stress of BMSCs by Activating PI3K/AKT Signaling.

Objective Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) remains a hopeful therapeutic approach for bone defect reconstruction. Herein, we investigated the effects and mechanisms of leukemia inhibitory factor (LIF) in the function and viability of hypoxic BMSCs as well as bone defect repair. Methods The effects of LIF on apoptosis (flow cytometry, TUNEL staining), mitochondrial activity (JC-1 staining), proliferation (colony formation, EdU staining), and differentiation (CD105, CD90, and CD29 via flow sorting) were examined in hypoxic BMSCs. LIF, LIFR, gp130, Keap1, Nrf2, antioxidant enzymes (SOD1, catalase, GPx-3), bone-specific matrix proteins (ALP, BSP, OCN), PI3K, and Akt were detected via immunoblotting or immunofluorescent staining. BMSCs combined with biphasic calcium phosphate scaffolds were implanted into calvarial bone defect mice, and the therapeutic effect of LIF on bone defect was investigated. Results Hypoxic BMSCs had increased apoptosis and oxidative stress and reduced mitochondrial activity. Additionally, LIF, LIFR, and gp130 were upregulated and PI3K/Akt activity was depressed in hypoxic BMSCs. Upregulated LIF alleviated apoptosis and oxidative stress and heightened mitochondrial activity and PI3K/Akt signaling in hypoxic BMSCs. Additionally, LIF overexpression promoted self-renewal and osteogenic differentiation of BMSCs with hypoxic condition. Mechanically, LIF facilitated self-renewal and differentiation as well as attenuated oxidative stress of BMSCs through enhancing PI3K/AKT signaling activity. Implantation of LIF-overexpressed BMSC-loaded BCP scaffolds promoted osteogenesis as well as alleviated oxidative stress and apoptosis through PI3K/Akt signaling. Conclusion Our findings demonstrate that LIF facilitates self-renewal and differentiation and attenuates oxidative stress of BMSCs by PI3K/AKT signaling.

Osteocondritis dissecans lesions of the knee restored by bone marrow aspirate concentrate. Clinical and imaging results in 18 patients

BackgroundOsteochondritis dissecans (OCD) is a common cartilage disorder that specifically affects the knees of skeletally immature and young adult patients. There have been a few treatments that have been proposed: fixation of the fragment, drilling, microfractures. The aim of this study was to analyze retrospectively clinical and imaging results obtained by treating it with one-step bone marrow-derived cells Transplantation (BMDCT) technique.MethodsFrom 2007 to 2014, 18 patients (mean-age 19.1 ± 5.0 years) affected by OCD were treated with one-step BMDC transplantation. In our observational study, clinical evaluation was performed at a scheduled follow-up through IKDC, Tegner, KOOS and EQ-VAS. X-rays and MRI were conducted preoperatively and at 12 months. At final follow-up, MRI MOCART Score was evaluated.ResultsIKDC and KOOS clinical scores showed a progressive increase. Tegner Score at final follow-up (5.3 ± 2.7) was significantly lower compared to the pre-injury level (6.5 ± 2.1); however, these results showed a statistically significant improvement that remained over time. EQ-VAS showed a significant improvement in every follow-up measure. MRI Mocart Score showed a complete or almost complete filling of the lesion in 13 patients.Conclusions“One-step” technique allows articular surface restoration with viable physiologic osteochondral tissue with a high clinical efficacy and imaging results. The number of cases is still limited, and further studies with larger sample sizes and greater follow-up evaluations are required to confirm our results. Nevertheless, we believe that BMDCT may represent a suitable option to treat OCD lesion in young adults.

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

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.

Tetramethylpyrazine induces the release of BDNF from BM-MSCs through activation of the PI3K/AKT/CREB pathway.

Compelling evidences suggest that transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) can be therapeutically effective for central nervous system (CNS) injuries and neurodegenerative diseases. The therapeutic effect of BM-MSCs mainly attributes to their differentiation into neuron-like cells which replace injured and degenerative neurons. Importantly, the neurotrophic factors released from BM-MSCs can also rescue injured and degenerative neurons, which plays a biologically pivotal role in enhancing neuroregeneration and neurological functional recovery. Tetramethylpyrazine (TMP), the main bioactive ingredient extracted from the traditional Chinese medicinal herb Chuanxiong, has been reported to promote the neuronal differentiation of BM-MSCs. This study aimed to investigate whether TMP regulates the release of neurotrophic factors from BM-MSCs. We examined the effect of TMP on brain-derived neurotrophic factor (BDNF) released from BM-MSCs and elucidated the underlying molecular mechanism. Our results demonstrated that TMP at concentrations of lower than 200 μM increased the release of BDNF in a dose-dependent manner. Furthermore, the effect of TMP on increasing the release of BDNF from BM-MSCs was blocked by inhibiting the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/cAMP-response element binding protein (CREB) pathway. Therefore, we concluded that TMP could induce the release of BDNF from BM-MSCs through activation of the PI3K/AKT/CREB pathway, leading to the formation of neuroprotective and proneurogenic microenvironment. These findings suggest that TMP possesses novel therapeutic potential to promote neuroprotection and neurogenesis through improving the neurotrophic ability of BM-MSCs, which provides a promising nutritional prevention and treatment strategy for CNS injuries and neurodegenerative diseases via the transplantation of TMP-treated BM-MSCs.

Quantitative MRI T2 Mapping is Able to Assess Tissue Quality After Reparative and Regenerative Treatments of Osteochondral Lesions of the Talus.

BackgroundQuantitative MRI has potential for tissue characterization after reparative and regenerative surgical treatment of osteochondral lesions of the talus (OCLTs). However available data is inconclusive and quantitative sequences can be difficult to implement in real‐time clinical application.PurposeTo assess the potential of T2 mapping in discriminating articular tissue characteristics after reparative and regenerative surgery of OCLTs in real‐world clinical settings.Study TypeObservational and prospective cohort study.Population15 OCLT patients who had received either reparative treatment with arthroscopic microfracture surgery (MFS) for a grade I lesion or regenerative treatment with bone marrow derived cell transplantation (BMDCT) for a grade II lesion.Field Strength/Sequence1.5 T, proton density weighted TSE, T2‐weighted true fast imaging with steady‐state‐free precession and multi‐echo T2 mapping sequences.AssessmentPatients were evaluated at a minimum postoperative follow‐up of 24 months. T2 maps of the ankle were generated and the distribution of T2 values was analyzed in manually identified volumes of interest (VOIs) for both treated lesions (TX) and healthy cartilage (CTRL). The amount of fibrocartilage, hyaline‐like and remodeling tissue in TX VOIs was obtained, based on T2 thresholds from CTRL VOIs.Statistical TestsFisher's exact test for categorical data, nonparametric Mann–Whitney U test for continuous data. The statistical significance level was P < 0.05.ResultsFrom CTRL VOI analysis, T2 < 25 msec, 25 msec ≤ T2 ≤ 45 msec, and T2 > 45 msec were considered as representative for fibrocartilage, hyaline‐like and remodeling tissue, respectively. Tissue composition of the two treatment groups was different, with significantly more fibrocartilage (+28%) and less hyaline‐like tissue (−15%) in MFS than in BMDCT treated lesions. No difference in healthy tissue composition was found between the two groups (P = 0.75).Data ConclusionsT2 mapping of surgically treated OCLTs can provide quantitative information about the type and amount of newly formed tissue at the lesion site, thereby facilitating surgical follow‐up in a real‐word clinical setting.Level of Evidence2Technical EfficacyStage 3

Osteochondral Lesions of the Distal Tibial Plafond: A Systematic Review of Lesion Locations and Treatment Outcomes.

Background:Osteochondral lesions of the tibial plafond (OLTPs) remain less common than osteochondral lesions of the talus (OLTs), but recognition of the condition has increased.Purpose:To systematically evaluate the literature on lesion locations and treatment outcomes of OLTPs, whether in isolation or in combination with OLTs.Study Design:Systematic review; Level of evidence, 4.Methods:A search was performed using the PubMed, Embase, and CINAHL databases for studies on lesion locations or with imaging or treatment outcomes of OLTPs. Case reports and reports based on expert opinion were excluded. Lesion locations as well as outcome measure results were aggregated. The Methodological Index for Non-randomized Studies score was used to assess methodological quality when applicable.Results:Included in this review were 10 articles, all published in 2000 or later. Most studies were evidence level 4, and the mean Methodological Index for Non-randomized Studies score was 8.6 (range, 8-10). Overall, 174 confirmed OLTP cases were identified, and the mean patient age was 38.8 years. Of the 157 lesions with confirmed locations, the most common was central-medial (32/157; 20.4%). Of 6 studies on treatment outcomes, all but 1 evaluated bone marrow stimulation techniques. Microfracture of small lesions (<150 mm2) was the most common treatment utilized. Imaging and functional outcomes appeared favorable after treatment. The data did not support differences in outcomes between isolated OLTPs and OLTPs with coexisting OLTs.Conclusion:Osteochondral lesions of the distal tibia most commonly occurred at the central-medial tibial plafond. Microfracture of small lesions was the most common treatment utilized, and clinical and magnetic resonance imaging results were favorable, although data were heterogeneous. Areas for future research include the following: the effect of patient factors and additional pathologies on outcomes; larger or deeper lesion treatment; more direct comparisons of outcomes between kissing or coexisting lesions and isolated lesions; and head-to-head comparison of treatments, such as microfracture, bone marrow–derived cell transplantation, and osteochondral autografts/allografts.

Neurotrophin-3 Promotes the Neuronal Differentiation of BMSCs and Improves Cognitive Function in a Rat Model of Alzheimer's Disease.

Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) has the potential to be developed into an effective treatment for neurodegenerative diseases such as Alzheimer's disease (AD). However, the therapeutic effects of BMSCs are limited by their low neural differentiation rate. We transfected BMSCs with neurotrophin-3 (NT-3), a neurotrophic factor that promotes neuronal differentiation, and investigated the effects of NT-3 gene overexpression on the differentiation of BMSCs into neurons in vitro and in vivo. We further studied the possible molecular mechanisms. We found that overexpression of NT-3 promoted the differentiation of BMSCs into neurons in vitro and in vivo and improved cognitive function in rats with experimental AD. By contrast, silencing NT-3 inhibited the differentiation of BMSCs and decreased cognitive function in rats with AD. The Wnt/β-catenin signaling pathway was involved in the mechanism by which NT-3 gene modification influenced the neuronal differentiation of BMSCs in vitro and in vivo. Our findings support the prospect of using NT-3-transduced BMSCs for the development of novel therapies for AD.

Bone marrow-derived mesenchymal stem cells improve post-ischemia neurological function in rats via the PI3K/AKT/GSK-3β/CRMP-2 pathway

Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) is a potential therapy for cerebral ischemia. However, the underlying protective mechanism remains undetermined. Here, we tested the hypothesis that transplantation of BMSCs via intravenous injection can alleviate neurological functional deficits through activating PI3K/AKT signaling pathway after cerebral ischemia in rats. A cerebral ischemic rat model was established by the 2h middle cerebral artery occlusion (MCAO). Twenty-four hours later, BMSCs (1 × 106 in 1ml PBS) from SD rats were injected into the tail vein. Neurological function was evaluated by modified neurological severity score (mNSS) and modified adhesive removal test before and on d1, d3, d7, d10 and d14 after MCAO. Protein expressions of AKT, GSK-3β, CRMP-2 and GAP-43 were detected by Western-bolt. NF-200 was detected by immunofluorescence. BMSCs transplantation did not only significantly improve the mNSS score and the adhesive-removal somatosensory test after MCAO, but also increase the density of NF-200 and the expression of p-AKT, pGSK-3β and GAP-43, while decrease the expression of pCRMP-2. Meanwhile, these effects can be suppressed by LY294002, a specific inhibitor of PI3K/AKT. These data suggest that transplantation of BMSCs could promote axon growth and neurological deficit recovery after MCAO, which was associated with activation of PI3K/AKT /GSK-3β/CRMP-2 signaling pathway.

Transplantation of bone marrow-derived mesenchymal stem cells with silencing of microRNA-138 relieves pelvic organ prolapse through the FBLN5/IL-1β/elastin pathway.

Nondegradable transvaginal polypropylene meshes for treating pelvic organ prolapse (POP) are now generally unavailable or banned due to serious adverse events. New tissue engineering approaches combine degradable scaffolds with mesenchymal stem/stromal cells from human endometrium (eMSC). In this study, we investigate effect of microRNA-138 (miR-138) regulation on bone marrow-derived mesenchymal stem cells (BMSCs) and the efficacy of BMSC transplantation therapy in a rat POP model. We first identified FBLN5 as a target of miR-138. miR-138, fibulin-5 (FBLN5), interleukin-1β (IL-1β), and elastin expression in uterosacral ligament of POP patients and controls were detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. After isolation and identification, BMSCs were treated to alter their expression of miR-138 or FBLN5. Proliferation of BMSCs was analyzed by CCK-8. After establishing the rat pelvic floor dysfunction (PFD) model, we evaluated efficacy of BMSC injection by applying leak point pressure (LPP) and the conscious cystometry (CMG) tests. miR-138 inhibition resulted in increased viability of BMSCs and elevated their secretion of elastin, while downregulating IL-1β expression. BMSCs with inhibited miR-138 improved LPP and conscious CMG results in vivo. Taken together, miR-138 could be a potential therapeutic target for treating POP in conjunction with tissue engineering.