Adult clinical trials have reported safety and the therapeutic potential of stem cells for cardiac disease. These observations have now translated to the pediatric arena. We conducted a meta-analysis to assess safety and efficacy of cell-based therapies in animal and human studies of pediatric heart disease.

Stroke is one of the main causes of death and disability worldwide. Cell therapy represents a promising therapeutic approach to improve stroke outcome. Measurement of blood-based biomarkers might serve as a proof-of-concept to monitor the mechanisms undergirding these treatments, and such compounds could be used as surrogate biomarkers to monitor the safety and efficacy of cell therapies in the future. Additionally, the measurement of biomarkers that correlate with circulating stem cells in observational studies might be of interest to improve the understanding of how these cells are spontaneously mobilized and carry out their action after stroke. Thus, a systematic review has been herein performed on blood-based biomarkers assessed in stroke patients treated with cell therapy or in observational studies in which circulating stem cells have been measured after stroke.

Adipose tissue is a rich source of stem cells, which are reported to represent 2% of the stromal vascular fraction (SVF). The infrapatellar fat pad (IFP) is a unique source of tissue, from which human adipose-derived stem cells (hADSCs) have been shown to harbour high chondrogenic potential. This review aims to calculate, based on the literature, the culture time needed before an average knee articular cartilage defect can be treated using stem cells obtained from arthroscopically or openly harvested IFP. Firstly, a systematic literature review was performed to search for studies that included the number of stem cells isolated from the IFP. Subsequent analysis was conducted to identify the amount of IFP tissue harvestable, stem cell count and the overall yield based on the harvesting method. We then determined the minimum time required before treating an average-sized knee articular cartilage defect with IFP-derived hADSCs by using our newly devised equation. The amount of fat tissue, the SVF cell count and the stem cell yield are all lower in arthroscopically harvested IFP tissue compared to that collected using arthrotomy. As an extrapolation, we show that an average knee defect can be treated in 20 or 17 days using arthroscopically or openly harvested IFP-derived hADSCs, respectively. In summary, the systematic review conducted in this study reveals that there is a higher amount of fat tissue, SVF cell count and overall yield (cells/volume or cells/gram) associated with open (arthrotomy) compared to arthroscopic IFP harvest. In addition to these review findings, we demonstrate that our novel framework can give an indication about the culture time needed to scale up IFP-derived stem cells for the treatment of articular cartilage defects based on harvesting method.

Myelomeningocele (MMC) is a spinal cord congenital defect that leads to paraplegia, bladder incontinence and bowel dysfunction. A randomized human trial demonstrated that in utero surgical repair of the MMC defect improves lower limb motor function. However, functional recovery remains incomplete. Stem cell therapy has recently generated great interest in the field of prenatal repair of MMC. In this systematic review we attempt to provide an overview of the current application of stem cells in different animal models of MMC. Publications were retrieved from PubMed and Cochrane Library databases. This process yielded twenty-two studies for inclusion in this review, experimenting five different types of stem cells: human embryonic stem cells, neural stem cells, induced pluripotent stem cells, human amniotic fluid stem cells, and mesenchymal stem cells (MSCs). Rodents and ovine were the two major species used for animal model studies. The source, the aims, and the main results were analyzed. Stem cell therapy appears to be a promising candidate for prenatal repair of MMC, especially MSCs. Further explorations in ovine and rodent models, reporting clinical and functional results, are necessary before an application in humans.

Sickle cell disease is a genetic disorder involving a defect in the red blood cells due to its sickled hemoglobin. The main therapeutic interventions include preventive and supportive measures. Hematopoietic stem cell transplantations are carried out with the aim of replacing the defective cells and their progenitors (hematopoietic (i.e. blood forming) stem cells) in order to correct the disorder. This is an update of a previously published review.

Extensive dental and periodontal defects are frequent and with a limited regenerative potential. Tissue engineering could be a promising tool to obtain personalized oral grafts. However, current research shows a lack of in vitro engineered oral tissues. This is explained by the difficulty to engineer blood vessel systems, impairing the connection to the host tissue and the graft success. Various strategies were used to engineer vascularized tissues and reported successful results, thus needing a clear analysis of the current state of art in oral tissue engineering. This systematic review aimed at studying the critical factors and techniques used to engineer a prevascularized oral tissue graft. PubMed, Cochrane Library, and SCOPUS databases were searched over the last 5 years following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Out of 638 screened studies, 24 were included in the systematic review according to strict inclusion and exclusion criteria and focusing on higher connection to the host vasculature. Animal models were all rodents, and subcutaneous implantation was the most used intervention. Studies presented low-to-unclear risk of bias according to the Systematic Review Center for Laboratory Animal Experimentation tool. Endothelial cells were mainly human umbilical vein endothelial cells, while stromal cells were most of the time oral or mesenchymal stem cells. Coculture of both types of cells at a 1:1 ratio was the most common technique used to obtain vascular networks, and some studies precultured grafts up to 3 weeks to enable network formation before implantation. Prevascularized grafts were produced by various tissue engineering technologies, including cell seeding and/or embedding, cell sheets, and spheroids. All studies reported a statistically significant faster and higher connection to host of prevascularized constructs compared to controls. Vessel networks were indeed denser, with a higher portion of lumen containing erythrocytes and blood flow increased. By assessing the relevant studies on the subject, this systematic review showed that engineered prevascularization proved to be an interesting approach to improve graft connection to the host vasculature and respective specific cell and scaffold criteria. Further studies on enhanced scaffolds and larger animals seem necessary to confirm these promising results with more voluminous grafts and get closer to native human tissues and applications. Impact statement Autologous oral grafts display limitations in terms of revascularization and morbidity of donor sites, despite being the gold standard. This systematic review aimed at clarifying existing data regarding techniques to engineer prevascularized oral grafts. Tissue engineering techniques, using cocultures of endothelial and oral stromal cells, proved to be an efficient way to enhance and accelerate the connection of the graft to the host vasculature. Engineered prevascularization appears to be a promising way to improve the connection to the host and the vascularization of grafts, especially when voluminous. Large animal and human studies are necessary to allow clinical translation.

Given the limitations of current therapies for the reconstruction of bone defects, regenerative medicine has arisen as a new therapeutic strategy along with mesenchymal stem cells (MSCs), which, because of their osteogenic potential and immunomodulatory properties, have emerged as a promising alternative for the treatment of bone injuries. In vivo studies have demonstrated that MSCs have a positive effect on regeneration due to their secretion of cytokines and growth factors that, when collected in conditioned medium (MSC-CM) and applied to an injured tissue, can modulate and promote the formation of new tissue.

This systematic review assessed if photobiomodulation of human dental pulp tissue improved cell viability, proliferation, and/or differentiation compared with a placebo. This systematic review was conducted in line with PRISMA. PICO question was established; inclusion and exclusion criteria were established before a search had begun. A literature search was conducted through PubMed, Scopus, and Cochrane. Studies were included if published within the last 20 years in English language, or where translation was available; laser parameters were mentioned; human dental pulp tissue was studied in vitro. Studies were excluded if non-human dental pulp tissue was studied and where the study was an in vivo study. Out of the total 121 studies found, 109 were excluded. Of the twelve included studies, three full-text articles were not available despite attempts made to contact the respective authors, leaving nine studies. Four of the included studies reported the use of stem cells derived from human deciduous teeth (SHEDs), and five used those from human permanent teeth (DPSCs). Most included studies utilized InGaAlP laser with wavelengths 660 nm, and one study with 610 nm. Other types of lasers included LED InGaN, and GaAlAs. Out of all included studies, two had a moderate risk of bias, and the rest had a low risk of bias. All studies confirmed positive effects on proliferation. One study also found improved osteogenic differentiation of the stem cells derived from stem cells of deciduous teeth. After assessing SHEDs and DPSCs separately, it is found that photobiomodulation improved cell proliferation in both subgroups. Due to heterogeneity in design protocols and laser parameters, it was not possible to compare the studies together. However, this study indicated that cell viability and proliferation did improve with photobiomodulation.

Mesenchymal stem cells (MSCs) have appeared as a promising regenerative cell-based therapeutic, for degenerative conditions, such as OA, while the beneficial results from the application of MSCs have been attributed to the MSCs-derived secretome, which is the sum of cytoprotective factors produced by the MSCs. Aim of this study was to systematically review the literature in order to assess whether stem cell secretome (conditioned medium-CM, exosome-Exos or microvesicles-MV)(CM/Exos/MVs) treatment reduces inflammation and enhances cartilage regeneration in preclinical studies of experimental arthritis.

Abstract　　Umbilical cord blood (UCB) is an alternative source of hematopoietic stem cells (HSCs) for patients who were lack of HLA match related or unrelated donors. Compared with bone marrow and mobilized peripheral blood, UCB has the advantages of easy availability, safety for donors, and low requirement for HLA match between donors and recipients. However, the cell amount in UCB is relatively less, which was associated with increased graft failure, delayed hematologic recovery, immune reconstitution, and higher transplant related mortality after UCB transplantation (UCBT). Double-unit UCB is a straightforward method to augment cell amount in UCB. Compared with single-unit UCBT, double-unit CBT associated with less risk of primary disease relapse and increased incidence rate of graft-versus-host disease (GVHD), but the hematologic recovery and overall survival of recipients were no significantly difference between single and double-unit UCBT. Novel strategies for UCB expansion significantly increased the cell amount in UCB, single-unit expanded UCBT not only increased the sources of UCB, but also decreased the high cost of double-unit UCB. ATG can decrease the risk of graft failure and GVHD rate, but the role of ATG in UCBT is still controversial. Herein, the recent clinical advances on UCBT in the treatment of hematologic diseases are systematically reviewed.

Stroke is the second leading cause of death worldwide. There is a real need to develop treatment strategies for reducing neurological deficits in stroke survivors, and stem cell (SC) therapeutics appear to be a promising alternative for stroke therapy that can be used in combination with approved thrombolytic or thrombectomy approaches. However, the efficacy of SC therapy depends on the SC homing ability and engraftment into the injury site over a long period of time. Nonetheless, tracking SCs from their niche to the target tissues is a complex process.

Articular cartilage defect of the knee is a debilitating disease and marrow stimulation techniques (MST) is typically regarded as the first line of treatment for full thickness cartilage lesions. However, the ability of MST to induce the repair of cartilage defects with fibrocartilage is limited, raising concerns about the durability of the repaired tissue. Mesenchymal stem cells (MSCs) provide an alternative means of treating cartilage defects. Expanded MSCs transplantation following MST has achieved great success in animal studies, but relevant clinical results are still lacking.

Mesenchymal stem cells (MSCs) transplantation has been considered a possible therapeutic method for Multiple Sclerosis (MS). However, no quantitative data synthesis of MSCs therapy for MS exists. We conducted a systematic review and meta-analysis to evaluate the effects of MSCs in experimental autoimmune encephalomyelitis (EAE) animal model of MS.

The process of aging influences every bodily organ and tissue, and those with rapid epithelial cell turnover, are particularly affected. The most visible of these, however, is the skin (including the epidermis), the largest human organ that provides a barrier to external insults, structure to the body and its movements, facilitates thermoregulation, harbors immune cells, and incorporates sensory neurons (including mechanoreceptors, nociceptors, and thermoreceptors). Skin aging has traditionally been categorized into intrinsic and extrinsic, with the latter nearly exclusively restricted to "photoaging," (i.e., aging due to exposure to solar or artificial ultraviolet radiation). However, both intrinsic and extrinsic aging share similar causes, including oxidative damage, telomere shortening, and mitochondrial senescence. Also, like other malignancies, the risk of malignant and nonmalignant lesions increases with age. Herein, we review the most recent findings in skin aging and nonmelanoma skin cancer, including addition to traditional and developing therapies.

Stem cell-based regenerative medicine is a promising approach for tissue reconstruction. However, a large number of cells are needed in a typical clinical study, where conventional monolayer cultures might pose a limitation for scale-up. The purpose of this review was to systematically assess the application of microcarriers in Mesenchymal Stem Cell cultures. A comprehensive search was conducted in Medline via Ebscohost, Pubmed, and Scopus, and relevant studies published between 2015 and 2019 were selected. The literature search identified 53 related studies, but only 14 articles met the inclusion criteria. These include 7 utilised commercially available microcarriers, while the rest were formulated based on different surface characteristics, all of which are discussed in this review. Current applications of microcarriers were focused on MSC expansion and induction of MSCs into different lineages. These studies demonstrated that MSCs could proliferate in a microcarrier culture system in-fold compared to monolayer cultures, and the culture system could simulate a three-dimensional environment which induces cell differentiation. However, detailed studies are still required before this system were to be adapted into the scale of GMP manufacturing.

Cancer stem cells (CSCs) have been reported in various hematopoietic and solid tumors, therefore, are considered to promote cancer progression, metastasis, recurrence and drug resistance. However, regulation of CSCs at the molecular level is not fully understood. microRNAs (miRNAs) have been identified as key regulators of CSCs by modulating their major functions: self-renewal capacity, invasion, migration and proliferation. Various studies suggest that metformin, an anti-diabetic drug, has an anti-tumor activity but its precise mechanism of action has not been understood. The present article was written in accordance to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We systematically reviewed evidence for metformin's ability to eradicate CSCs through modulating the expression of miRNAs in various solid tumors. PubMed and MEDLINE were searched from January 1990 to January 2020 for in vitro studies. Two authors independently selected and reviewed articles according to predefined eligibility criteria and assessed risk of bias of included studies. Four papers met the inclusion criteria and presented low risk bias. All of the included studies reported a suppression of CSCs' major function after metformin dosage. Moreover, it was showed that metformin anti-tumor mechanism of action is based on regulation of miRNAs expression. Metformin inhibited cell survival, clonogenicity, wound-healing capacity, sphere formation and promotes chemosensitivity of tumor cells. Due to the small number of publications, aforementioned evidences are limited but may be consider as background for clinical studies.

In recent years, photobiomodulation therapy (PBMT) has found many applications in various medical fields. Studies of PBMT on spinal cord injury (SCI) have mostly used laser sources in experimental animal models. The purpose of this study was to summarize studies that have employed PBMT for various kinds of SCI in animals. A thorough search in databases including MEDLINE, EMBASE, SCOPUS, and Web of Science, with the removal of unrelated articles, yielded 16 relevant articles. The meta-analysis showed that PBMT was effective in improving post-SCI movement in the first 14 days (MD = 1.593 (95% CI: 1.110 to 2.075; p <0.001, I2 = 51.9%) and this improvement became even greater thereafter (MD = 2.086 (95% CI: 1.570 to 2.603; p = <0.001. I2= 90.3%). Time of irradiation (<300 sec or >300 sec), gender (male or female), injury model (contusion or compression, radiation protocol (<14 days or ≥14days), laser wavelength (<800nm or >800nm) and injury severity (moderate or severe) were found to be factors that can affect PBM efficacy for SCI treatment. PBMT has an anti-inflammatory effect, is effective in reducing the size of spinal cord lesions and helps to absorb administrated proteins and stem cells to the lesion site.

To perform a systematic review and meta-analysis evaluating the effects of mesenchymal stem cells (MSCs) on cartilage regeneration and patient-reported pain and function.

Severe cases of COVID-19 infection, often leading to death, have been associated with variants of acute respiratory distress syndrome (ARDS). Cell therapy with mesenchymal stromal cells (MSCs) is a potential treatment for COVID-19 ARDS based on preclinical and clinical studies supporting the concept that MSCs modulate the inflammatory and remodeling processes and restore alveolo-capillary barriers. The authors performed a systematic literature review and random-effects meta-analysis to determine the potential value of MSC therapy for treating COVID-19-infected patients with ARDS. Publications in all languages from 1990 to March 31, 2020 were reviewed, yielding 2691 studies, of which nine were included. MSCs were intravenously or intratracheally administered in 117 participants, who were followed for 14 days to 5 years. All MSCs were allogeneic from bone marrow, umbilical cord, menstrual blood, adipose tissue, or unreported sources. Combined mortality showed a favorable trend but did not reach statistical significance. No related serious adverse events were reported and mild adverse events resolved spontaneously. A trend was found of improved radiographic findings, pulmonary function (lung compliance, tidal volumes, PaO2 /FiO2 ratio, alveolo-capillary injury), and inflammatory biomarker levels. No comparisons were made between MSCs of different sources.

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML). APL is famed with some special blood coagulation disorders such as disseminated intravascular coagulation (DIC). The therapeutic methods of APL contain All Trans Retinoic Acid (ATRA), arsenic trioxide (ATO) or/and chemotherapy. Many studies have been done on APL blood disorders and its treatment. These studies have shown different results. In this systematic article, we tried to review the effect of ATO therapy with or without ATRA and chemotherapy on DIC parameters (D-dimer, Prothrombin Time, Activated Partial Thrombin Time, Platelet count) in APL patients. The result of included studies demonstrated that although ATO can reduce the number of malignant cells in the bone marrow and peripheral blood, it does not have enough potential to attenuate the danger of high score DIC that is usual in APL patients and should be better to be used with other therapeutic methods.