The 2019 novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has occurred in China and around the world. SARS-CoV-2-infected patients with severe pneumonia rapidly develop acute respiratory distress syndrome (ARDS) and die of multiple organ failure. Despite advances in supportive care approaches, ARDS is still associated with high mortality and morbidity. Mesenchymal stem cell (MSC)-based therapy may be an potential alternative strategy for treating ARDS by targeting the various pathophysiological events of ARDS. By releasing a variety of paracrine factors and extracellular vesicles, MSC can exert anti-inflammatory, anti-apoptotic, anti-microbial, and pro-angiogenic effects, promote bacterial and alveolar fluid clearance, disrupt the pulmonary endothelial and epithelial cell damage, eventually avoiding the lung and distal organ injuries to rescue patients with ARDS. An increasing number of experimental animal studies and early clinical studies verify the safety and efficacy of MSC therapy in ARDS. Since low cell engraftment and survival in lung limit MSC therapeutic potentials, several strategies have been developed to enhance their engraftment in the lung and their intrinsic, therapeutic properties. Here, we provide a comprehensive review of the mechanisms and optimization of MSC therapy in ARDS and highlighted the potentials and possible barriers of MSC therapy for COVID-19 patients with ARDS.
Adoptive Transfer ; Alveolar Epithelial Cells ; pathology ; Animals ; Apoptosis ; Betacoronavirus ; Body Fluids ; metabolism ; CD4-Positive T-Lymphocytes ; immunology ; Clinical Trials as Topic ; Coinfection ; prevention & control ; therapy ; Coronavirus Infections ; complications ; immunology ; Disease Models, Animal ; Endothelial Cells ; pathology ; Extracorporeal Membrane Oxygenation ; Genetic Therapy ; methods ; Genetic Vectors ; administration & dosage ; therapeutic use ; Humans ; Immunity, Innate ; Inflammation Mediators ; metabolism ; Lung ; pathology ; physiopathology ; Mesenchymal Stem Cell Transplantation ; methods ; Mesenchymal Stem Cells ; physiology ; Multiple Organ Failure ; etiology ; prevention & control ; Pandemics ; Pneumonia, Viral ; complications ; immunology ; Respiratory Distress Syndrome, Adult ; immunology ; pathology ; therapy ; Translational Medical Research

In the conventional concept of translational research, investigations flow from the laboratory bench to the bedside. However, clinical research can also serve as the starting point for subsequent laboratory investigations that then lead back to the bedside. This article chronicles the evolution of a series of studies in which a detailed analysis of pharmacokinetics in hemodialysis patients revealed new physiological insight that, through a systems approach incorporating kinetic, physicochemical, physiologic, and clinical trial results, led to an elucidation of the pathophysiology of intradialytic skeletal muscle cramps. Based on this understanding, a therapeutic path forward is proposed.
Humans ; Muscle Cramp ; Muscle, Skeletal ; Pharmacokinetics ; Renal Dialysis ; Renin-Angiotensin System ; Sympathetic Nervous System ; Systems Analysis ; Translational Medical Research

The stem/progenitor cell has long been regarded as a central cell type in development, homeostasis, and regeneration, largely owing to its robust self-renewal and multilineage differentiation abilities. The balance between self-renewal and stem/progenitor cell differentiation requires the coordinated regulation of cell cycle progression and cell fate determination. Extensive studies have demonstrated that cell cycle states determine cell fates, because cells in different cell cycle states are characterized by distinct molecular features and functional outputs. Recent advances in high-resolution epigenome profiling, single-cell transcriptomics, and cell cycle reporter systems have provided novel insights into the cell cycle regulation of cell fate determination. Here, we review recent advances in cell cycle-dependent cell fate determination and functional heterogeneity, and the application of cell cycle manipulation for cell fate conversion. These findings will provide insight into our understanding of cell cycle regulation of cell fate determination in this field, and may facilitate its potential application in translational medicine.
Animals ; Cell Cycle ; Cell Physiological Phenomena ; Epigenomics ; G1 Phase ; G2 Phase ; Humans ; Translational Medical Research

Preoperative chemo- and radiotherapeutic strategies followed by surgery are currently a standard approach for treating locally advanced gastric and esophagogastric junction cancer in Western countries. However, in a large number of cases, the tumor is extremely resistant to these treatments and the patients are exposed to unnecessary toxicity and delayed surgical therapy. The current clinical trials evaluating the combination of preoperative systemic therapies with modern targeted and immunotherapeutic agents represent a unique opportunity for identifying predictive biomarkers of response to select patients that would benefit the most from these treatments. However, it is of utmost importance that these potential biomarkers are corroborated by extensive preclinical and translational research. The aim of this review article is to present the most promising biomarkers of response to classic chemotherapeutic, anti-HER2, antiangiogenic, and immunotherapeutic agents that can be potentially useful for personalized preoperative systemic therapies in gastric cancer patients.
Biomarkers ; Esophagogastric Junction ; Humans ; Microsatellite Instability ; Receptor, Fibroblast Growth Factor, Type 3 ; Stomach Neoplasms ; Translational Medical Research

Neonatal hypoxic-ischemic (HI) brain injury is a major cause of neonatal mortality and long-term neurodevelopmental disabilities. Although promising neuroprotective interventions have been studied, the current management of HI brain injury has been limited to supportive measures and induced hypothermia. In addition to engrafting, migrating toward the damage sites and differentiating into multiple lineages, multipotent neural stem/progenitor cells (NSPCs) also provide trophic/immunomodulatory factors and integrate into the host neurons upon implantation into an HI-injured brain. However, NSPC-based therapies have shown poor cell survival and integration, poor differentiation or restricted differentiation into the glial lineages. Furthermore, to achieve full functional recovery following brain injury, the optimization of cell therapy is needed to recapitulate the precise migration of stem cells to the region of interest and the neural rewiring present in the brain microenvironment. Therefore, the efficacy of NSPCs in the treatment of CNS injury is currently insufficient. Human NSPCs (hNSPCs) were isolated from the forebrain of an aborted fetus at 13 weeks of gestation with full parental consent and the approval of the Institutional Review Board of the Yonsei University College of Medicine. Here, to enhance the regenerative ability of hNSPCs in HI brain injury, cells were either pretreated with pharmacological agents or engineered to serve as vehicles for gene delivery. Furthermore, when combined with a poly (glycolic acid)-based synthetic scaffold, hNSPCs provide a more versatile treatment for neonatal HI brain injury. Finally, hNSPCs transfected with zinc-doped ferrite magnetic nanoparticles for controlling both cell migration and differentiation offer a simple and smart tool for cell-based therapies.
Aborted Fetus ; Brain Injuries ; Brain ; Cell Movement ; Cell Survival ; Cell- and Tissue-Based Therapy ; Ethics Committees, Research ; Genetic Therapy ; Humans ; Hypothermia, Induced ; Hypoxia-Ischemia, Brain ; Infant ; Infant Mortality ; Nanoparticles ; Neural Stem Cells ; Neurons ; Parental Consent ; Pregnancy ; Prosencephalon ; Stem Cells ; Translational Medical Research

Trigeminal nerve injury as a consequence of lower third molar surgery is a notorious complication and may affect the patient in long term. Inferior alveolar nerve (IAN) and lingual nerve (LN) injury result in different degree of neurosensory deficit and also other neurological symptoms. The long term effects may include persistent sensory loss, chronic pain and depression. It is crucial to understand the pathophysiology of the nerve injury from lower third molar surgery. Surgery remains the most promising treatment in moderate-to-severe nerve injuries. There are limitations in the current treatment methods and full recovery is not commonly achievable. It is better to prevent nerve injury than to treat with unpredictable results. Coronectomy has been proved to be effective in reducing IAN injury and carries minimal long-term morbidity. New technologies, like the roles of erythropoietin and stem cell therapy, are being investigated for neuroprotection and neural regeneration. Breakthroughs in basic and translational research are required to improve the clinical outcomes of the current treatment modalities of third molar surgery-related nerve injury.
Chronic Pain ; Depression ; Erythropoietin ; Humans ; Lingual Nerve ; Mandibular Nerve ; Molar, Third ; Neuroprotection ; Postoperative Complications ; Regeneration ; Stem Cells ; Translational Medical Research ; Trigeminal Nerve Injuries ; Trigeminal Nerve

This article reviews the available published data on optimizing clopidogrel and aspirin therapy using translational and integrative medicine. Translational and evidence-based medical studies show that the CYP2C19 gene mutation (CYP2C19*2 and CYP2C19*3) could affect > 50% of the Chinese population, and that this mutation is closely associated with clopidogrel resistance and an increased risk of major adverse cardiovascular events, particularly stent thrombosis in patients following percutaneous coronary intervention (PCI). Adjusted-dose warfarin and aspirin reduce stroke in patients with atrial fibrillation (AF), and warfarin is substantially more efficacious than aspirin. However, a poor compliance is a big problem in warfarin use especially in China. The genetic variants of vitamin K expoxide reductase might account for the universally lower warfarin dosage used in Chinese population. The available evidence indicates that the integrating mainstream treatments (e.g., clopidogrel, CYP2C19 genotyping) and non-mainstream medicines [e.g., Chinese medicines, Naoxintong Capsule (, NXT)] to treat CYP2C19 gene mutation patients following PCI can be effective. Aspirin combined NXT and the adjusted-dose warfarin was equally effective in elderly patients with non-valvular AF in prevention of ischemic stroke.
Aspirin ; therapeutic use ; Clopidogrel ; therapeutic use ; Humans ; Integrative Medicine ; Translational Medical Research

Fast progresses in stem cell-based tooth tissue engineering have been achieved in recent years in several animal models including the mouse, rat, dog, and pig. Moreover, various postnatal mesenchymal stem cells of dental origin have been isolated and shown capable of differentiating into odontoblasts and generating dentin. Meanwhile, human keratinocyte stem/progenitor cells, gingival epithelial cells, and even iPSC-derived epithelium have been demonstrated to be able to differentiate into functional ameloblasts. Translational medicine studies in the nonhuman primate are irreplaceable steps towards clinical application of stem cell-based tissue engineering therapy. In the present study, we first examined the epithelial stem cell markers in the rhesus skin using immunostaining. Keratinocyte stem cells were then isolated from rhesus epidermis, cultured in vitro, and characterized by epithelial stem cell markers. Epithelial sheets of these cultured keratinocytes, which were recombined with E13.5 mouse dental mesenchyme that possesses odontogenic potential in the presence of exogenous FGF8, were induced to differentiate into enamel-secreting ameloblasts. Our results demonstrate that in the presence of appropriate odontogenic signals, rhesus keratinocytes can be induced to gain odontogenic competence and are capable of participating in odontogenesis, indicating that rhesus keratinocytes are an ideal epithelial cell source for further translational medicine study of tooth tissue engineering in nonhuman primates.
Ameloblasts* ; Animals ; Dentin ; Dogs ; Epidermis ; Epithelial Cells ; Epithelium ; Humans ; In Vitro Techniques ; Keratinocytes* ; Macaca mulatta ; Mental Competency ; Mesenchymal Stromal Cells ; Mesoderm* ; Mice* ; Models, Animal ; Odontoblasts ; Odontogenesis ; Primates ; Rats ; Skin ; Stem Cells ; Tissue Engineering ; Tooth ; Translational Medical Research

Cancer stem cells (CSCs), a subpopulation of tumor cells, have self-renewal and multi-lineage differentiation abilities that play an important role in cancer initiation, maintenance, and metastasis. An accumulation of evidence indicates that CSCs can cause conventional therapy failure and cancer recurrence because of their treatment resistance and self-regeneration characteristics. Therefore, approaches that specifically and efficiently eliminate CSCs to achieve a durable clinical response are urgently needed. Currently, treatments with chimeric antigen receptor-modified T (CART) cells have shown successful clinical outcomes in patients with hematologic malignancies, and their safety and feasibility in solid tumors was confirmed. In this review, we will discuss in detail the possibility that CART cells inhibit CSCs by specifically targeting their cell surface markers, which will ultimately improve the clinical response for patients with various types of cancer. A number of viewpoints were summarized to promote the application of CSC-targeted CART cells in clinical cancer treatment. This review covers the key aspects of CSC-targeted CART cells against cancers in accordance with the premise of the model, from bench to bedside and back to bench.
Humans ; Molecular Targeted Therapy ; methods ; Neoplasms ; immunology ; pathology ; therapy ; Neoplastic Stem Cells ; pathology ; Receptors, Chimeric Antigen ; metabolism ; T-Lymphocytes ; immunology ; metabolism ; Translational Medical Research

Traumatic spinal cord injury (SCI) research has recently focused on the use of rat and mouse models for in vivo SCI experiments. Such small rodent SCI models are invaluable for the field, and much has been discovered about the biologic and physiologic aspects of SCI from these models. It has been difficult, however, to reproduce the efficacy of treatments found to produce neurologic benefits in rodent SCI models when these treatments are tested in human clinical trials. A large animal model may have advantages for translational research where anatomical, physiological, or genetic similarities to humans may be more relevant for pre-clinically evaluating novel therapies. Here, we review the work carried out at the University of British Columbia (UBC) on a large animal model of SCI that utilizes Yucatan miniature pigs. The UBC porcine model of SCI may be a useful intermediary in the pre-clinical testing of novel pharmacological treatments, cell-based therapies, and the “bedside back to bench” translation of human clinical observations, which require preclinical testing in an applicable animal model.
Animals ; British Columbia ; Humans ; Mice ; Models, Animal ; Rats ; Rodentia ; Spinal Cord Injuries ; Spinal Cord ; Swine ; Translational Medical Research