Stem cell injection for knee osteoarthritis (KOA) is an emerging new therapy, and we aimed to review its evidence of efficacy.

The applications for fat grafting have increased recently, within both regenerative and reconstructive surgery. Although fat harvesting, processing and injection techniques have been extensively studied and standardised, this has not had a big impact on the variability of outcome following fat grafting. This suggests a possible larger role of patient characteristics on adipocyte and adipose-derived stem cell (ADSC) viability and function. This systematic review aims to collate current evidence on the effect of patient factors on adipocyte and ADSC behaviour.

Several non-biological materials are currently being used to increase the alveolar bone volume to support dental implants. Recently, stem cell therapy has emerged as a promising biological substitute or adjuvant to enhance bone healing. In order to determine if stem cell therapy has enough clinical evidence to bone ridge augmentation in humans, a systematic review and meta-analysis were conducted. Two independent investigators searched the Entrez PubMed, SCOPUS and Web of Science databases for eligible randomized clinical trials that describe stem cell therapies for alveolar bone formation. The included studies were evaluated for risk of bias. A random-effects meta-analysis model was used to evaluate the percentage of bone formation in the selected studies. Heterogeneity was evaluated using the Cochrane Chi 2 and I 2. Nine eligible trials were included. These studies presented an overall unclear risk of bias. A comparison between the lower heterogeneity studies and the long term observational outcomes showed a slight tendency to enhance bone formation. High heterogeneity between the included studies was observed. The lack of outcome standardization made a wide-ranging comparison difficult. The application of stem cells in oral surgery and implantology appears to be promising although more standardized study designs, increased samples and long-term observations are needed to strength the clinical evidence that stem cell therapy is effective for alveolar bone formation.

The current systematic review investigated the results of application of some of the most commonly used scaffolds in conjugation with stem cells and growth factors in animal and clinical studies.

The introduction of mesenchymal stromal cells (MSCs) has changed the management of Crohn's fistula, while it remains controversial. The aim of this study was to provide an overview of efficacy and optimum state of MSCs treatment on Crohn's fistula.

Cell-therapy has been promoted among the therapeutic arsenal that can aid in bone formation and remodeling, in early stages of osteonecrosis of the femoral head (ONFH). The purpose of this systematic review was to assess the evidence supporting the (1) clinical efficacy; (2) structural modifying effect, as evaluated radiographically; (3) revision rates; and (4) safety of cell-therapy for the treatment of ONFH.

Today, autogenous bone graft (ABG) is still considered as the gold standard for joint fusion. Recombinant human platelet-derived growth factor-BB (rhPDGF-BB) which is of chemotactic and mitogenic to mesenchymal stem cells and possesses outstanding osteogenetic potentials has been used for ankle and foot fusion in recent years. The goal of this article is to evaluate the safety and efficacy of rhPDGF-BB versus ABG in foot and ankle fusion. The PubMed MEDLINE, EMBASE, Web of Science, and Cochrane Library were systematic searched. Finally, three randomized controlled trials (RCTs) with 634 patients were enrolled in this study. Results of radiologic effectiveness which included CT and radiographic union rates revealed that there was no significant difference between rhPDGF-BB approach and ABG approach. Analysis of clinical results held the same outcomes expect that ABG group was superior in long-term Short Form-12 physical component scores. The pooled results also demonstrated that rhPDGF-BB was as safe as ABG in foot and ankle surgery. However, autograft harvesting procedure has some drawbacks such as donor-site pain and morbidity, additional operation time, blood loss, and scarring, which can be overcome by rhPDGF-BB. Thus, rhPDGF-BB is a viable alternative to autograft in foot and ankle fusion surgery. Yet, more high-quality RCTs with long-term follow-up are still required to make the final conclusion.

The maintenance of viable and functional pancreatic islets is crucial for successful islet transplantation from brain-dead donors. To overcome islet quality loss during culture, some studies have co-cultured islets with mesenchymal stem/stromal cells (MSC). However, it is still uncertain if MSC-secreted factors are enough to improve islet quality or if a physical contact between MSCs and islets is needed. Therefore, we performed a systematic review and meta-analysis to clarify the effect of different culture contact systems of islets with MSCs on viability and insulin secretion outcomes. Pubmed and Embase were searched. Twenty studies fulfilled the eligibility criteria and were included in the qualitative synthesis and/or meta-analysis. For both outcomes, pooled weighted mean differences (WMD) between islet cultured alone (control group) and the co-culture condition were calculated. Viability mean was higher in islets co-cultured with MSCs compared with islet cultured alone [WMD = 18.08 (95% CI 12.59-23.57)]. The improvement in viability was higher in islets co-cultured in indirect or mixed contact with MSCs than in direct physical contact (P <0.001). Moreover, the mean of insulin stimulation index (ISI) was higher in islets from co-culture condition compared with islet cultured alone [WMD = 0.83 (95% CI 0.54-1.13)], independently of contact system. Results from the studies that were analyzed only qualitatively are in accordance with meta-analysis data. Co-culture of islets with MSCs has the potential for protecting islets from injury during culture period. Moreover, culture time appears to influence the beneficial effect of different methods of co-culture on viability and function of islets.

Mesenchymal stromal cells (MSCs) are considered to have a modest benefit on left ventricular ejection fraction (LVEF) in patients with acute myocardial infarction (AMI). However, the optimal injection timing and dose needed to induce beneficial cardiac effects are unknown. The purpose of this meta-analysis was to identify an optimal MSC transplantation time and cell dose in the setting of AMI to achieve better clinical endpoints.

CD19, CD20 chimeric antigen receptor T (CAR T) cell therapy has shown promising results for the treatment of relapsed or refractory hematological malignancies. Best results have been reported in acute lymphoblastic leukemia patients with a complete response rate above 80%. Patients who received donor-derived CAR T cells for the relapsed malignancy after stem cell transplantation (allogenic hematopoietic stem cell transplant) were identified from the published trials. A total of 72 patients from seven studies were treated with donor-derived CAR T cells. Only five out of 72 patients (6.9%) developed graft versus host disease. Use of donor-derived CAR T cell for relapse prophylaxis, minimal residual disease clearance or salvage from relapse is therefore highly effective, and risk of graft versus host disease flare is very low. Side effects include cytokine release syndrome, tumor lysis syndrome, B-cell aplasia along with CNS toxicity.

Pericytes are an integral cellular component of vascular structures. Numerous studies have investigated various stem cell types as potential sources of pericytes for application in cell-based therapy. The diverse stem cell types and variable experimental protocols of these studies make it imperative to evaluate the relevant scientific literature on the basis of a unified standard. The purpose of this systematic review is to rigorously evaluate the relevant scientific literature for conclusive evidence that stem cells can differentiate into functional pericytes. An online literature search was conducted up to July 2016. Eligible papers were evaluated on 4 pertinent criteria: 1) appropriate controls, 2) markers to confirm pericyte phenotype, 3) techniques for assessing pericyte functionality, and 4) differentiation efficiency of the protocol. Our search yielded 20 eligible studies (from 2006 to 2016), 12 of which were published in the past 5 yr. Of these 20 articles, only 1 had positive control, and 5 papers evaluated differentiation efficiency. The most commonly used pericyte markers were neuron-glial antigen 2, platelet-derived growth factor receptor-β, and α-smooth muscle actin. Three articles were associated with adipose stem cells, 4 with mesenchymal stem cells, and 7 with pluripotent stem cells, whereas the remaining 6 articles were based on other miscellaneous stem cell types. Stem cells can serve as a potential source of pericytes, but there should be standardized guidelines in future studies for assessing pericyte differentiation.-Xu, J., Gong, T., Heng, B. C., Zhang, C. F. A systematic review: differentiation of stem cells into functional pericytes.

Development is an epigenetic regulation dependent event. As one pretranscriptional regulator, bivalent histone modifications were observed to be involved in development recently. It is believed that histone methylation potentially takes charge of cell fate determination and differentiation. The synchronous existence of functionally opposite histone marks at transcript start sequence (TSS) is defined as "Bivalency", which mainly mark development related genes. H3K4me3 and H3K27me3, the prominent histone methylations of bivalency, are implicated in transcriptional activation and transcriptional repression respectively. The delicate balance between H3K4me3 and H3K27me3 produces diverse chromatin architectures, resulting in different transcription states of downstream genes: "poised", "activated" or "repressed".

High post-transplantation cell mortality is the main limitation of various approaches that are aimed at improving regeneration of injured neural tissue by an injection of neural stem cells (NSCs) and mesenchymal stromal cells (MStroCs) in and/or around the lesion. Therefore, it is of paramount importance to identify efficient ways to increase cell transplant viability. We have previously proposed the "evolutionary stem cell paradigm," which explains the association between stem cell anaerobic/microaerophilic metabolic set-up and stem cell self-renewal and inhibition of differentiation. Applying these principles, we have identified the main critical point in the collection and preparation of these cells for experimental therapy: exposure of the cells to atmospheric O2, that is, to oxygen concentrations that are several times higher than the physiologically relevant ones. In this way, the primitive anaerobic cells become either inactivated or adapted, through commitment and differentiation, to highly aerobic conditions (20%-21% O2 in atmospheric air). This inadvertently compromises the cells' survival once they are transplanted into normal tissue, especially in the hypoxic/anoxic/ischemic environment, which is typical of central nervous system (CNS) lesions. In addition to the findings suggesting that stem cells can shift to glycolysis and can proliferate in anoxia, recent studies also propose that stem cells may be able to proliferate in completely anaerobic or ischemic conditions by relying on anaerobic mitochondrial respiration. In this systematic review, we propose strategies to enhance the survival of NSCs and MStroCs that are implanted in hypoxic/ischemic neural tissue by harnessing their anaerobic nature and maintaining as well as enhancing their anaerobic properties via appropriate ex vivo conditioning.

Critical limb ischemia is a life-threatening complication of peripheral arterial disease. In patients who are ineligible for revascularization procedures, there are few therapeutic alternatives, leading to amputations and death.

The regeneration and establishment of osseointegration within oral peri-implant bone defects remains a clinical challenge. Bone tissue engineering (BTE) is emerging as a promising alternative to autogenous and/or biomaterial-based bone grafting. The objective of this systematic review was to answer the focused question: in animal models, do cell-based BTE strategies enhance bone regeneration and/or implant osseointegration in experimental peri-implant defects, compared with grafting with autogenous bone or only biomaterial scaffolds? Electronic databases were searched for controlled animal studies reporting on peri-implant defects and implantation of mesenchymal stem cells (MSC) or other cells seeded on biomaterial scaffolds, following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Random effects meta-analyses were performed for the outcomes histomorphometric bone area fraction (BA) and bone-to-implant contact (BIC). Nineteen studies reporting on large animal models (dogs and sheep) were included. Experimental defects were created surgically (16 studies) or via ligature-induced peri-implantitis (LIPI, three studies). In general, studies presented with an unclear to high risk of bias. In most studies, MSC were used in combination with alloplastic mineral phase or polymer scaffolds; no study directly compared cell-loaded scaffolds vs. autogenous bone. In three studies, cells were also modified by ex vivo gene transfer of osteoinductive factors. The meta-analyses indicated statistically significant benefits in favour of: (a) cell-loaded vs. cell-free scaffolds [weighted mean differences (WMD) of 10.73-12.30% BA and 11.77-15.15% BIC] in canine surgical defect and LIPI models; and (b) gene-modified vs. unmodified cells (WMD of 29.44% BA and 16.50% BIC) in canine LIPI models. Overall, heterogeneity in the meta-analyses was high (I2 70-88%); considerable variation was observed among studies regarding the nature of cells and scaffolds used. In summary, bone regeneration and osseointegration in peri-implant defects are enhanced by the addition of osteogenic cells to biomaterial scaffolds. Although the direction of treatment outcome is clearly in favour of BTE strategies, due to the limited magnitude of treatment effect observed, no conclusive statements regarding the clinical benefit of such procedures for oral indications can yet be made. Copyright © 2017 John Wiley & Sons, Ltd.

Allogeneic haematopoietic stem cell transplant (HSCT) recipients are at increased risk of morbidity and mortality, often due to the development of acute or chronic graft-versus-host disease (GVHD). Low numbers or proportions of regulatory T cells (Tregs) have been reported in patients who develop GVHD. We undertook a systematic review of studies that reported the Treg composition of HSCT grafts in patients with haematological malignancies. Fourteen eligible studies were identified, eight of which stratified patients by Tregs (absolute dose or ratio to CD3+ or CD4+ cells). Meta-analyses showed that high levels of Tregs in the grafts were associated with improved overall survival [hazard ratio (HR) 0·42, 95% confidence interval (CI) 0·23-0·74, P = 0·003, 2 studies], with a significant reduction in non-relapse mortality (HR 0·30, 95% CI 0·14-0·64, P = 0·002, 2 studies) and a reduced risk of acute GVHD (relative risk (RR) 0·59, 95% CI 0·40-0·89, P = 0·01, 6 studies). The consistency of these findings strongly suggests that the Treg composition of HSCT grafts has a powerful effect on the success of allogeneic HSCT. The major challenge is to translate these findings into better selection of allografts and future donors to provide a substantial improvement in allogeneic HSCT outcomes and practice.

Cell dose limits greater use of umbilical cord blood (UCB) in hematopoietic cell transplantation. The clinical benefits of ex vivo expansion need clarity to understand its potential impact. A systematic search of studies addressing UCB ex vivo expansion was conducted. Fifteen clinical studies (349 transplanted patients) and 13 registered trials were identified. The co-infusion of an expanded unit and a second unmanipulated unit (8 studies), the fractional expansion of 12% to 60% of a single unit (5 studies), and the infusion of a single expanded unit (2 studies) were reported. More recently, published studies and 12 of 13 ongoing trials involve the use of novel small molecules in addition to traditional cytokine cocktails. Higher total cell number was closely associated with faster neutrophil engraftment. Compared with historical controls, neutrophil engraftment was significantly accelerated in more recent studies using small molecules or mesenchymal stromal cells (MSC) co-culture, and in some cases, platelet recovery was also statistically improved. Recent studies using nicotinamide and StemRegenin-1 reported long-term chimerism of the expanded unit. No significant improvement in survival or other transplant-related outcomes was demonstrated for any of the strategies. Ex vivo expansion of UCB can accelerate initial neutrophil engraftment after transplant. More recent studies suggest that long-term engraftment of ex vivo expanded cord blood units is achievable. Results of larger randomized controlled trials are needed to understand the impact on patient outcomes and health care costs.

Intraoperative application of the stromal vascular fraction (SVF) of adipose tissue requires a fast and efficient isolation procedure of adipose tissue. This review was performed to systematically assess and compare procedures currently used for the intraoperative isolation of cellular SVF (cSVF) and tissue SVF (tSVF) that still contain the extracellular matrix. Pubmed, EMBASE and the Cochrane central register of controlled trials databases were searched for studies that compare procedures for intraoperative isolation of SVF (searched 28 September 2016). Outcomes of interest were cell yield, viability of cells, composition of SVF, duration, cost and procedure characteristics. Procedures were subdivided into procedures resulting in a cSVF or tSVF. Thirteen out of 3038 studies, evaluating 18 intraoperative isolation procedures, were considered eligible. In general, cSVF and tSVF intraoperative isolation procedures had similar cell yield, cell viability and SVF composition compared to a nonintraoperative (i.e. culture laboratory-based collagenase protocol) control group within the same studies. The majority of intraoperative isolation procedures are less time consuming than nonintraoperative control groups, however. Intraoperative isolation procedures are less time-consuming than nonintraoperative control groups with similar cell yield, viability of cells and composition of SVF, and therefore more suitable for use in the clinic. Nevertheless, none of the intraoperative isolation procedures could be designated as the preferred procedure to isolate SVF. Copyright © 2017 John Wiley & Sons, Ltd.

Stem cells have emerged as a new treatment option for tendon disorders. We systematically reviewed the current evidence for stem cell therapy in tendon disorders.

Cell assisted lipotransfer serves as a novel technique for both breast reconstruction and breast augmentation. This systematic review assesses the efficacy, safety and use of patient reported outcome measures in studies involving cell assisted lipotransfer. We also carry out an objective assessment of study quality focussing on recruitment, follow-up and provide an up-to-date clinical trial landscaping analysis.