The effects of combined low level laser therapy and mesenchymal stem cells on bone regeneration in rabbit calvarial defects

Abstract: This study evaluated the effect of Low Level Laser Therapy (LLLT) and Mesenchymal Stem Cells (MSCs) on bone regeneration. Background data: Although several studies evaluated the effects of MSCs and LLLT, there is little information available regarding in vivo application of LLLT in conjunction with MSCs. Methods: Forty-eight circular bone defects (6 mm in diameter) were prepared in the calvaria of 12 New- Zealand white rabbits. The defects of each animal were randomly assigned to 4 groups: (C) no treatment; (L) applying LLLT; (SC) filled with MSCs; (SCL) application of both MSCs and LLLT. LLL was applied on alternate days at wavelength of 810 nm, power density of 0.2 W/cm2 and a fluency of 4 J/cm2 using a Gallium–Aluminum–Arsenide (GaAlAs) diode laser. The animals were sacrificed after 3 weeks and then histological samples were evaluated to determine the amount of new bone formation and the remaining scaffold and inflammation. Results: The histological evaluation showed a statistically significant increase in new bone formation of LLLT group relative to the control and the other two experimental groups (p < 0.05). There was no significant difference in bone formation of the control group compared to experimental groups filled with MSCs. Laser irradiation had no significant effect on resorption of the scaffold material. In addition, inflammation was significantly reduced in LLLT group compared to the control defects and the other two experimental groups. Conclusion: Low level laser therapy could be effective in bone regeneration but there is no evidence of a synergistic effect when applied in conjunction with MSCs

TLR-4 ligation of dendritic cells is sufficient to drive pathogenic T cell function in experimental autoimmune encephalomyelitis

<p>Abstract</p> <p>Background</p> <p>Experimental autoimmune encephalomyelitis (EAE) depends on the initial activation of CD4⁺ T cells responsive to myelin autoantigens. The key antigen presenting cell (APC) population that drives the activation of naïve T cells most efficiently is the dendritic cell (DC). As such, we should be able to trigger EAE by transfer of DC that can present the relevant autoantigen(s). Despite some sporadic reports, however, models of DC-driven EAE have not been widely adopted. We sought to test the feasibility of this approach and whether activation of the DC by toll-like receptor (TLR)-4 ligation was a sufficient stimulus to drive EAE.</p> <p>Findings</p> <p>Host mice were seeded with myelin basic protein (MBP)-reactive CD4+ T cells and then were injected with DC that could present the relevant MBP peptide which had been exposed to lipopolysaccharide as a TLR-4 agonist. We found that this approach induced robust clinical signs of EAE.</p> <p>Conclusions</p> <p>DC are sufficient as APC to effectively drive the differentiation of naïve myelin-responsive T cells into autoaggressive effector T cells. TLR-4-stimulation can activate the DC sufficiently to deliver the signals required to drive the pathogenic function of the T cell. These models will allow the dissection of the molecular requirements of the initial DC-T cell interaction in the lymphoid organs that ultimately leads to autoimmune pathology in the central nervous system.</p

Erratum: COMPARE CPM-RMI trial: Intramyocardial transplantation of autologous bone marrow-derived CD133+ cells and MNCs during CABG in patients with recent MI: A phase II/III, multicenter, placebo-controlled, randomized, double-blind clinical trial. (Cell Journal (2018) 20:3 (449) DOI: 10.22074/cellj.2018.5197)

This article published in Cell J (Yakhteh), Vol 20, No 2, Jul-Sep 2018, on pages 267-277, four affiliations (1, 4, 5, and 10) were changed based on authors request. © 2018 Royan Institute (ACECR). All rights reserved

COMPARE CPM-RMI Trial: Intramyocardial transplantation of autologous bone marrow-derived CD133+ Cells and MNCs during CABG in patients with recent MI: A Phase II/III, multicenter, placebo-controlled, randomized, double-blind clinical trial

Objective: The regenerative potential of bone marrow-derived mononuclear cells (MNCs) and CD133+ stem cells in the heart varies in terms of their pro-angiogenic effects. This phase II/III, multicenter and double-blind trial is designed to compare the functional effects of intramyocardial autologous transplantation of both cell types and placebo in patients with recent myocardial infarction (RMI) post-coronary artery bypass graft. Materials and Methods: This was a phase II/III, randomized, double-blind, placebo-controlled trial COMPARE CPM-RMI (CD133, Placebo, MNCs - recent myocardial infarction) conducted in accordance with the Declaration of Helsinki that assessed the safety and efficacy of CD133 and MNCs compared to placebo in patients with RMI. We randomly assigned 77 eligible RMI patients selected from 5 hospitals to receive CD133+ cells, MNC, or a placebo. Patients underwent gated single photon emission computed tomography assessments at 6 and 18 months post-intramyocardial transplantation. We tested the normally distributed efficacy outcomes with a mixed analysis of variance model that used the entire data set of baseline and between-group comparisons as well as within subject (time) and group�time interaction terms. Results: There were no related serious adverse events reported. The intramyocardial transplantation of both cell types increased left ventricular ejection fraction by 9 95% confidence intervals (CI): 2.14% to 15.78%, P=0.01 and improved decreased systolic wall thickening by -3.7 (95% CI: -7.07 to -0.42, P=0.03). The CD133 group showed significantly decreased non-viable segments by 75% (P=0.001) compared to the placebo and 60% (P=0.01) compared to the MNC group. We observed this improvement at both the 6- and 18-month time points. Conclusion: Intramyocardial injections of CD133+ cells or MNCs appeared to be safe and efficient with superiority of CD133+ cells for patients with RMI. Although the sample size precluded a definitive statement about clinical outcomes, these results have provided the basis for larger studies to confirm definitive evidence about the efficacy of these cell types (Registration Number: NCT01167751). © 2018 Royan Institute (ACECR). All Rights Reserved

In-vitro differentiation of human embryonic stem cells into hemangioblasts

Background: Human embryonic stem cells (hESCs) are capable of self-renewal and large-scale expansion. They also have the capacity to differentiate into a variety of cell types including liver, cardiac and neuron cells. However, it is not yet clear whether hESCs can differentiate to hemangioblasts under in-vitro conditions. Hemangioblasts are bipotential progenitors that can generate hematopoietic lineages and endothelial cells. The aim of this study was to identify the potential of human Royan H5 embryonic stem cells in differentiating into hemangioblast cells. Methods: HESCs were cultured at suspension system in DMEM/F12 supplemented with bFGF. 7-day old cells differentiated into blast cells under defined condition consisting of hematopoietic cytokines including BMP4, VEGF, etc. Blast cell markers kinase insert domain receptor (KDR), CD31, and CD34 were evaluated by flow cytometry and blast gene expressions (TAL-1, Runx-1 and CD34) were detected by qRT-PCR. Clonogenic assays were performed in semisolid medium by colony forming unit-assays. Results: The hESCs (Royan H5) had the capacity of differentiating into hemangioblast cells. We could detect colonies that expressed 79%±12.5 KDR+, 5.6%±2.8 CD31+-CD34+ and 6%±2.12 KDR+-CD31+ on day 8 in the hESCs. Up-regulation of TAL-1, Runx-1 and CD34 occurred during hemangioblast commitment (P≤0.05 and P≤0.01, respectively). Moreover, hemangioblast cells generated mixed-type and endothelial-like colonies in semi-solid media. Conclusion: Our results showed that hESCs (Royan H5) were able to differentiate into hemangioblasts under in-vitro conditions. The hemangioblasts had the potential to generate two non-adherent (Mixed-type) and adherent (endothelial-like) cell populations

Review. the Story of Melanocyte: Long Way From Bench to Bedside

Skin is composed of major layers, a superficial epidermis and a deeper dermis. The color of skin is influenced by a number of pigments, including melanin. Melanin is produced by cells called melanocytes. Most skin disorders are relatively benign, but a few, including melanomas, can be fatal. A couple of the more noticeable disorders, namely albinism and vitiligo, affect the appearance of the skin and its accessory organs. Vitiligo is associated with significant psychosocial morbidity and profound effect on quality of life. Topical steroids, calcineurin inhibitors, phototherapy and surgery are most common treatments. However, there are many patients who do not respond to any of these modalities. The transplantation of cultured or non-cultured melanocyte is the most important treatment for hypopigmentory disorders. In this study, we are going to assess the history of melanocyte cultivation and evaluate the effectiveness of transplantation cultured cells. We examined the beginning process of isolation, characterization, and transplantation of epidermal cells. This review, summarize our current understanding of the cutaneous pigmentary system from the start of synthesis in the pigment cells, along with the response of repigmentation. During the production of melanin, melanosomes are transferred to neighboring keratinocyte in order to form perinuclear melanin caps. The objective of this review is to analyze the melanocytes transplantation in the last century up to now, and how epidermal cells can increase pigmentation in hypo-pigmented areas in skin disorders. Also, we focus on the story of the melanocyte back to 1950. In addition, prior systemic therapy was associated with a significant increase significant increase based on combined additional therapy, achieving desired results and improved outcomes. Despite the short study of a long way of melanocyte assessment and follow up patient's treatment, results of the all reports were confirmed the efficacy of the used method in the treatment of stable vitiligo who did not respond to the common algorithms of non-invasive treatments

The correlation between endothelin-1 antibody plasma concentrations in patients with scleroderma and different manifestations of the disease

Background: Systemic scleroderma (SSc) is a generalized connective tissue disorder of unknown origin which most notably is characterized by skin thickening and organ damage. Endothelin-1 (ET-1) antibody plays a role in skin fibrosis. The aim of this study was to determine the prevalence and correlation of different manifestations of SSc with ET-1 plasma levels. Methods: This cross-sectional analytical study was conducted on 95 patients (91 women and four men) with scleroderma in 2006. The patients had been referred to the Rheumatology Clinic of Shariati Hospital in Tehran, Iran. The demographic data and signs and symptoms were entered in a questionnaire and endothelin-1 concentrations were measured. Results: The mean age of the patients was 38+12.29 years. Diffuse cutaneous SSc (dcSSc) was diagnosed in 52 and limited cutaneous SSc (lcSSc) in 43 patients. Raynaud's phenomenon (91%) was the most common manifestation in the patients. The relationship between the resorption of terminal phalanges due to fibrosis with the plasma concentration of Endothelin-1 was statistically significant (p=0.001). Pitting ulcers had significant relationships with endothelin-1 concentrations too (p<0.05). No other significant relationships were found between the other manifestation of the disease and Endothelin-1 concentration. Conclusion: In this study, Reynaud's phenomenon was the most frequent sign in patients with scleroderma. Thus, it could serve as a tool for the diagnosis of scleroderma. As there were no significant relationships between the other manifestations of scleroderma with endothelin-1, a cohort study with a larger sample size is suggested

A randomized, double-blind, phase I clinical trial of fetal cell-based skin substitutes on healing of donor sites in burn patients

Background: Due to limited graft donor sites in extensive burns, re-harvesting of a single donor area is very common. Given the importance of fetal fibroblasts in accelerating fetal wound healing, fetal cell-based skin substitutes have emerged as a novel therapeutic modality for regenerating damaged skin. In this trial, we aimed to evaluate the safety, feasibility and potential efficacy of application of amniotic membranes seeded with fetal fibroblasts for accelerating donor sites healing in burn patients. Methods: In this randomized, double-blind, phase I clinical trial, 10 patients with total burn surface area of 10�55 were enrolled. Three equal parts (10 � 10 cm) were selected in donor site of each patient and covered by Vaseline gauze (control group), amniotic membrane (AM group), or amniotic membrane seeded with fetal fibroblasts (AM-F group). Adverse events, pain intensity scores, and wound sizes were recorded on days 4, 8, 11, 14, and 20 post-treatment. Also, histological assessments were done on days 0 and 14 after the surgery. Results: All patients underwent surgery, and no adverse events occurred during the procedure and follow-up period. Significantly lower pain intensity and higher healing rates were observed in AM-F and AM groups compared to the control group. Moreover, mean complete re-epithelializatin in AM-F and AM groups were 10.1 ± 2.4 and 11.3 ± 2.9 days, showing that the healing process was significantly accelerated compared to the control group with mean closure time of 14.8 ± 1.6 days. Histological assessment showed lower inflammatory cells infiltration in AM-F and AM groups compared to control group. Conclusions: This study indicated the safety of transplantation of amniotic membrane seeded with fetal fibroblasts for treatment of donor sites in burn patients; however, preliminary assessments showed no benefits for this therapeutic modality over amniotic membrane alone. Thus, to draw accurate conclusions, further trials in larger populations should be conducted. Level of Evidence: This study is assigned as level I. © 201

Evaluation of safety, feasibility and efficacy of intra-ovarian transplantation of autologous adipose derived mesenchymal stromal cells in idiopathic premature ovarian failure patients: non-randomized clinical trial, phase I, first in human

Abstract Background Premature ovarian failure (POF) is characterized by the loss of ovarian activity before the age of 40 years. Stem cell therapy has the capability to create a regenerative microenvironment and is a proposed treatment for POF-related infertility due to the presence of renewal folliculogenesis and germ cells in the adult ovaries. In this study, we assessed the safety, feasibility, efficacy and dose adjustment of autologous adipose-derived stromal cells (ADSCs) and their ability to improve ovarian function in POF patients. Methods This study was a non-randomized clinical trial, phase I. Nine women with a definitive diagnosis of POF were divided into three groups (n = 3 per group) that received either 5 × 106, 10 × 106, or 15 × 106 autologous ADSCs suspension transplanted in the one ovary. Participants were followed-up at 24 h after the transplantation, and at 1 and 2 weeks, and 1, 2, 3, 6, and 12 months after the transplantation. The primary objective was to evaluate the safety of ADSCs transplantation. Secondary objectives included the effects of ADSCs transplantation on the resumption of menstruation, hormones level (Follicle-stimulating hormone (FSH) and anti-Müllerian hormone), ovarian function (Antral follicle count and ovary volume by ultrasonography evaluation) as well as dose escalation. Results Participants had not shown any early-onset possible side effects and secondary complications during follow-up. The menstruation resumption was observed in four patients which established for several months. In the 15 × 106 group, two POF patients had a return of menstruation second months after the intervention. Two other POF patients in 5 × 106 and 10 × 106 cell groups reported menstruation resumption at 1 month after the intervention. We observed decreased serum FSH levels of less than 25 IU/l in four patients. In two patients in 5 × 106 and 10 × 106 cell groups, serum FSH showed an inconsistent decline during a 1 year follow up after ADSCs transplantation. The ovarian volume, AMH, and AFC were variable during the follow-up and no significant differences between cell groups (p > 0.05). Conclusions We showed the intra-ovarian embedding of ADSCs is safe and feasible and is associated with an inconsistent decline in serum FSH. This should be further investigated with a large RCT. Trial registration NCT02603744 , Registered 13 November 2015 - Retrospectively registered, http://www.Clinicaltrials.go