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Effect of heterologous bone marrow mononuclear cell transplantation on midpalatal expansion in rats.

ABSTRACT: The aim of this study was to explore whether bone marrow mononuclear cell (BMMC) transplantation is able to accelerate the bone remodeling induced by midpalatal expansion in rats. A total of 48 male Sprague-Dawley rats (mean weight, 208.36±7.32 g) were divided into control and midpalatal expansion with or without BMMC transplantation groups. Histological and morphological changes were observed in each group. The osteogenic activities and differential potentials of the transplanted BMMCs labeled with bromodeoxyuridine in the midpalatal bone tissue were assessed by osteocalcin expression. The receptor activator of nuclear factor ?B ligand (RANKL)/osteoprotegerin (OPG) ratio was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to reflect the equilibrium between bone resorption and formation. The results demonstrated that the width of the maxillary dental arch increased distinctly within 2 weeks of midpalatal expansion with BMMC transplantation. The morphology of the midpalatal suture in this group changed significantly; the cartilage was completely replaced by fibrous-like tissue expressing osteocalcin. The palatal bone was reorganized from a cancellous form into a mature compact structure after an additional 2-week relapse period. Immunostaining results indicated that the heterologous transplanted BMMCs survived and differentiated into osteoblasts during the remodeling induced by midpalatal expansion. The RANKL/OPG expression ratio significantly decreased after 2 weeks of midpalatal expansion with BMMC transplantation due to the inhibition of RANKL expression. Heterologous BMMC transplantation appears to accelerate the midpalatal bone remodeling induced by expansion of the rats through increasing the number of osteoprogenitor cells and regulating the RANKL-OPG signaling pathway.

SUBMITTER: Guo J

PROVIDER: S-EPMC4353775 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Effect of heterologous bone marrow mononuclear cell transplantation on midpalatal expansion in rats.

Guo Jie J Wang Lue L Xu Haihua H Che Xiaoxia X

Experimental and therapeutic medicine 20150203 4

The aim of this study was to explore whether bone marrow mononuclear cell (BMMC) transplantation is able to accelerate the bone remodeling induced by midpalatal expansion in rats. A total of 48 male Sprague-Dawley rats (mean weight, 208.36±7.32 g) were divided into control and midpalatal expansion with or without BMMC transplantation groups. Histological and morphological changes were observed in each group. The osteogenic activities and differential potentials of the transplanted BMMCs labeled ...[more]

PMID: 25780415

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Project description:BACKGROUND:Insulin resistance and insulin deficiency are the cardinal defects in the pathogenesis of type 2 diabetes mellitus (T2DM). Despite the plethora of anti-diabetic medications, drugs specifically targeting the ?-cells are still desired. Stem cell therapy has emerged as a novel therapeutics strategy to target ?-cells; however, their mechanism of action has not been well defined. This study aims to examine the efficacy and safety of autologous bone marrow-derived mononuclear cells (ABM-MNCs) transplantation in T2DM, and explores the mechanistic insights into stem cells action through metabolic studies. METHODS:Seven T2DM patients with the duration of disease ?5 years, receiving triple oral anti-diabetic drugs along with insulin (?0.4 IU per kg per day) and HbA1c ? 7.5% (?58.0 mmol/mol) were enrolled for ABM-MNCs administration through a targeted approach. The primary end-point was a reduction in insulin requirement by ?50% from baseline, while maintaining HbA1c < 7.0% (<53.0 mmol/mol) with improvement in insulin secretion, and/or insulin sensitivity after ABM-MNCs transplantation. RESULTS:Six out of 7 (90%) patients achieved the primary end-point. At 6 months, there was a significant reduction in insulin requirement by 51% as compared to baseline (p < 0.003). This was accompanied by a significant increase in the 2nd phase C-peptide response during hyperglycemic clamp (p = 0.018), whereas there were no significant alterations in insulin sensitivity and glucose disposal rate during hyperinsulinemic-euglycemic clamp relative to the baseline. Other measures of ?-cell indices like HOMA-?, and stimulated C-peptide response to glucagon and mixed meal tolerance test were non-contributory. CONCLUSION:ABM-MNCs transplantation results in significant reduction in insulin doses and improvement in C-peptide response in patients with T2DM. Metabolic studies may be more useful than conventional indices to predict ?-cell function in patients with advanced duration of T2DM. Trial registration-Clinicaltrials.gov NCT01759823.

Project description:Transplantation of unfractionated bone marrow mononuclear cells (BMCs) repairs and/or regenerates the damaged myocardium allegedly due to secretion from surviving BMCs (paracrine effect). However, donor cell survival after transplantation is known to be markedly poor. This discrepancy led us to hypothesize that dead donor BMCs might also contribute to the therapeutic benefits from BMC transplantation. High mobility group box 1 (HMGB1) is a nuclear protein that stabilizes nucleosomes, and also acts as a multi-functional cytokine when released from damaged cells. We thus studied the role of extracellular HMGB1 in the effect of BMC transplantation for heart failure. Four weeks after coronary artery ligation in female rats, syngeneic male BMCs (or PBS only as control) were intramyocardially injected with/without anti-HMGB1 antibody or control IgG. One hour after injection, ELISA showed that circulating extracellular HMGB1 levels were elevated after BMC transplantation compared to the PBS injection. Quantitative donor cell survival assessed by PCR for male-specific sry gene at days 3 and 28 was similarly poor. Echocardiography and catheterization showed enhanced cardiac function after BMC transplantation compared to PBS injection at day 28, while this effect was abolished by antibody-neutralization of HMGB1. BMC transplantation reduced post-infarction fibrosis, improved neovascularization, and increased proliferation, while all these effects in repairing the failing myocardium were eliminated by HMGB1-inhibition. Furthermore, BMC transplantation drove the macrophage polarization towards alternatively-activated, anti-inflammatory M2 macrophages in the heart at day 3, while this was abolished by HMGB1-inhibition. Quantitative RT-PCR showed that BMC transplantation upregulated expression of an anti-inflammatory cytokine IL-10 in the heart at day 3 compared to PBS injection. In contrast, neutralizing HMGB1 by antibody-treatment suppressed this anti-inflammatory expression. These data suggest that extracellular HMGB1 contributes to the effect of BMC transplantation to recover the damaged myocardium by favorably modulating innate immunity in heart failure.

Project description:BackgroundOwing to the multifactorial nature of the pathogenesis of diabetic peripheral neuropathy (DPN), conventional drug therapies have not been effective. The application of stem cells transplantation may be useful for the treatment of DPN. This study was designed to assess the safety and therapeutic effects of autologous bone marrow mononuclear cells (BMMNCs) transplantation on the treatment of refractory DPN.MethodsOne hundred and sixty-eight patients with refractory DPN were recruited and enrolled in the study. They received intramuscular injection of BMMNCs and followed at 1, 3, 6, 12, 18, 24, and 36 months after the transplantation. Clinical data, Toronto Clinical Scoring System (TCSS), and nerve conduction studies (NCSs) were compared before and after the transplantation.ResultsThe signs and symptoms of neuropathy were significantly improved after BMMNCs transplantation. The values of the TCSS scores at 1 month (9.68 ± 2.49 vs. 12.55 ± 2.19, P < 0.001) and 3 months (8.47 ± 2.39 vs. 12.55 ± 2.19, P < 0.001) after the treatment reduced significantly compared with the baseline value. This decrement remained persistent until the end of the study. The conduction velocity and action potential and sensory nerves were significantly improved after transplantation (3 and 12 months after the treatment vs. the baseline: motor nerve conduction velocity, 40.24 ± 2.80 and 41.00 ± 2.22 m/s vs. 38.21 ± 2.28 m/s, P < 0.001; sensory nerve conduction velocity, 36.96 ± 2.26 and 39.15 ± 2.61 m/s vs. 40.41 ± 2.22 m/s, P < 0.001; compound muscle action potential, 4.67 ± 1.05 and 5.50 ± 1.20 μV vs. 5.68 ± 1.08 μV, P < 0.001; sensory nerve action potential, 4.29 ± 0.99 and 5.14 ± 1.26 μV vs. 5.41 ± 1.14 μV, P < 0.001). No adverse event associated with the treatment was observed during the follow-up period.ConclusionsAutologous transplantation of BMMNCs may be an effective and promising therapeutic strategy for the treatment of refractory DPN.

Project description:OBJECTIVE: Impaired liver regeneration is associated with a poor outcome in patients with decompensated alcoholic liver disease (ALD). We assessed whether autologous bone marrow mononuclear cell transplantation (BMMCT) improved liver function in decompensated ALD. DESIGN: 58 patients (mean age 54 yrs; mean MELD score 19, all with cirrhosis, 81% with alcoholic steatohepatitis at baseline liver biopsy) were randomized early after hospital admission to standard medical therapy (SMT) alone (n?=?30), including steroids in patients with a Maddrey's score ?32, or combined with G-CSF injections and autologous BMMCT into the hepatic artery (n?=?28). Bone marrow cells were harvested, isolated and reinfused the same day. The primary endpoint was a ?3 points decrease in the MELD score at 3 months, corresponding to a clinically relevant improvement in liver function. Liver biopsy was repeated at week 4 to assess changes in Ki67+/CK7+ hepatic progenitor cells (HPC) compartment. RESULTS: Both study groups were comparable at baseline. After 3 months, 2 and 4 patients died in the BMMCT and SMT groups, respectively. Adverse events were equally distributed between groups. Moderate alcohol relapse occurred in 31% of patients. The MELD score improved in parallel in both groups during follow-up with 18 patients (64%) from the BMMCT group and 18 patients (53%) from the SMT group reaching the primary endpoint (p?=?0.43 (OR 1.6, CI 0.49-5.4) in an intention to treat analysis. Comparing liver biopsy at 4 weeks to baseline, steatosis improved (p<0.001), and proliferating HPC tended to decrease in both groups (-35 and -33%, respectively). CONCLUSION: Autologous BMMCT, compared to SMT is a safe procedure but did not result in an expanded HPC compartment or improved liver function. These data suggest either insufficient regenerative stimulation after BMMCT or resistance to liver regenerative drive in patients with decompensated alcoholic cirrhosis. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN83972743.

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Effect of heterologous bone marrow mononuclear cell transplantation on midpalatal expansion in rats.

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Effect of heterologous bone marrow mononuclear cell transplantation on midpalatal expansion in rats.

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