Cell-processed therapeutic products (CTPs) derived from human pluripotent stem cells (hPSCs) have innovative applications in regenerative medicine. However, undifferentiated hPSCs possess tumorigenic potential; thus, sensitive methods for the detection of residual undifferentiated hPSCs are essential for the clinical use of hPSC-derived CTPs. The detection limit of the methods currently available is 1/105 (0.001%, undifferentiated hPSCs/differentiated cells) or more, which could be insufficient for the detection of residual hPSCs when CTPs contain more than 1 × 105 cells. In this study, we developed a novel approach to overcome this challenge, using adenovirus and adeno-associated virus (AdV and AAV)-based selective cytotoxic vectors. We constructed AdV and AAV vectors that possess a suicide gene, iCaspase 9 (iCasp9), regulated by the CMV promoter, which is dormant in hPSCs, for the selective expression of iCasp9 in differentiated cells. As expected, AdV/CMV-iCasp9 and AAV/CMV-iCasp9 exhibited cytotoxicity in cardiomyocytes but not in human induced pluripotent stem cells (hiPSCs). The vectors also induced apoptosis in hiPSC-derived cardiomyocytes, and the surviving cells exhibited higher levels of hPSC marker expression. These results indicate that the AdV- and AAV-based cytotoxic vectors concentrate cells expressing the undifferentiated cell markers in hiPSC-derived products and are promising biological tools for verifying the quality of CTPs.

Basic studies of human pluripotential stem cells have advanced rapidly and stem cell products are now seeing therapeutic applications. However, questions remain regarding the tumorigenic potential of such cells. Here, we report the tumorigenic potential of induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) for the treatment of wet-type, age-related macular degeneration (AMD). First, immunodeficient mouse strains (nude, SCID, NOD-SCID and NOG) were tested for HeLa cells' tumor-forming capacity by transplanting various cell doses subcutaneously with or without Matrigel. The 50% Tumor Producing Dose (TPD50 value) is the minimal dose of transplanted cells that generated tumors in 50% of animals. For HeLa cells, the TPD50 was the lowest when cells were embedded in Matrigel and transplanted into NOG mice (TPD50 = 10(1.1), n = 75). The TPD50 for undifferentiated iPSCs transplanted subcutaneously to NOG mice in Matrigel was 10(2.12); (n = 30). Based on these experiments, 1×10(6) iPSC-derived RPE were transplanted subcutaneously with Matrigel, and no tumor was found during 15 months of monitoring (n = 65). Next, to model clinical application, we assessed the tumor-forming potential of HeLa cells and iPSC 201B7 cells following subretinal transplantation of nude rats. The TPD50 for iPSCs was 10(4.73) (n = 20) and for HeLa cells 10(1.32) (n = 37) respectively. Next, the tumorigenicity of iPSC-derived RPE was tested in the subretinal space of nude rats by transplanting 0.8-1.5×10(4) iPSC-derived RPE in a collagen-lined (1 mm×1 mm) sheet. No tumor was found with iPSC-derived RPE sheets during 6-12 months of monitoring (n = 26). Considering the number of rodents used, the monitoring period, the sensitivity of detecting tumors via subcutaneous and subretinal administration routes and the incidence of tumor formation from the iPSC-derived RPE, we conclude that the tumorigenic potential of the iPSC-derived RPE was negligible.

Although a significant progress has been made in the management of ischemic heart disease (IHD), the number of severe IHD patients is increasing. Thus, it is crucial to develop new, non-invasive therapeutic strategies. In the present study, we aimed to develop low-intensity pulsed ultrasound (LIPUS) therapy for the treatment of IHD.

Dendritic cells (DC) play pivotal roles in regulating the immune system and inflammatory response. We previously reported DC infiltration in the infarcted heart and its immunoprotective roles in the post-infarction healing process after experimental myocardial infarction (MI). However, its clinical significance has not been determined.

Stem cells from human exfoliated deciduous teeth (SHED) transplants have been investigated as a possible treatment strategy for spinal cord injuries (SCI) due to their potential for promoting functional recovery. The aim of present study was to investigate the effects of SHED on neuronal death after an experimental model of SCI.

Human pluripotent stem cells (hPSCs) are leading candidate raw materials for cell-based therapeutic products (CTPs). In the development of hPSC-derived CTPs, it is imperative to ensure that they do not form tumors after transplantation for safety reasons. Because cellular immortalization is a landmark of malignant transformation and a common feature of cancer cells, we aimed to develop an in vitro assay for detecting immortalized cells in CTPs. We employed retinal pigment epithelial (RPE) cells as a model of hPSC-derived products and identified a gene encoding slow skeletal muscle troponin T (TNNT1) as a novel marker of immortalized RPE cells by comprehensive microarray analysis. TNNT1 mRNA was commonly upregulated in immortalized RPE cells and human induced pluripotent stem cells (hiPSCs), which have self-renewal ability. Additionally, we demonstrated that TNNT1 mRNA expression is higher in several cancer tissues than in normal tissues. Furthermore, stable expression of TNNT1 in ARPE-19 cells affected actin filament organization and enhanced their migration ability. Finally, we established a simple and rapid qRT-PCR assay targeting TNNT1 transcripts that detected as low as 3% of ARPE-19 cells contained in normal primary RPE cells. Purified hiPSC-derived RPE cells showed TNNT1 expression levels below the detection limit determined with primary RPE cells. Our qRT-PCR method is expected to greatly contribute to process validation and quality control of CTPs.

This article summarizes the recent activity of the International Stem Cell Banking Initiative (ISCBI) held at the California Institute for Regenerative Medicine (CIRM) in California (June 26, 2016) and the Korean National Institutes for Health in Korea (October 19-20, 2016). Through the workshops, ISCBI is endeavoring to support a new paradigm for human medicine using pluripotent stem cells (hPSC) for cell therapies. Priority considerations for ISCBI include ensuring the safety and efficacy of a final cell therapy product and quality assured source materials, such as stem cells and primary donor cells. To these ends, ISCBI aims to promote global harmonization on quality and safety control of stem cells for research and the development of starting materials for cell therapies, with regular workshops involving hPSC banking centers, biologists, and regulatory bodies. Here, we provide a brief overview of two such recent activities, with summaries of key issues raised. Stem Cells Translational Medicine 2017;6:1956-1962.

Unambiguous cell line authentication is essential to avoid loss of association between data and cells. The risk for loss of references increases with the rapidity that new human pluripotent stem cell (hPSC) lines are generated, exchanged, and implemented. Ideally, a single name should be used as a generally applied reference for each cell line to access and unify cell-related information across publications, cell banks, cell registries, and databases and to ensure scientific reproducibility. We discuss the needs and requirements for such a unique identifier and implement a standard nomenclature for hPSCs, which can be automatically generated and registered by the human pluripotent stem cell registry (hPSCreg). To avoid ambiguities in PSC-line referencing, we strongly urge publishers to demand registration and use of the standard name when publishing research based on hPSC lines.

The histological diagnosis of cardiac sarcoidosis (CS) is based on the presence of myocardial granulomas; however, the sensitivity of endomyocardial biopsy is relatively low. We investigated whether immunocompetent cells including dendritic cells (DC) and macrophages in nongranuloma sections of endomyocardial biopsy samples could be histopathological surrogates for CS diagnosis.

Cardiac sarcoidosis (CS) is a noncaseating granulomatous disease of unknown etiology. Lifelong immunosuppressive therapy, most frequently using corticosteroids, is a standard therapy to control hypersensitivity of immune reactions and prevent inflammation. However, it sometimes causes various systemic adverse effects and requires dose escalation. Thus, additional therapy may be required for the treatment of this disease. Recently, Propionibacterium acnes (P. acnes) was reported as one of the etiologic agents of CS, indicating that antibacterial drugs (ABD) may be effective for the treatment of CS. The objective of this study was to investigate the effect of ABD treatment, in addition to standard corticosteroid therapy, in patients with CS.

Although late gadolinium enhancement magnetic resonance imaging (LGE-MRI) allows the identification of lesions and gaps after a cryothermal balloon (CB) ablation of paroxysmal atrial fibrillation (PAF), the accuracy has not yet been well established.

Diabetes mellitus (DM) is associated with increased cardiovascular (CV) risk. We compared health-related quality of life (HRQoL), healthcare resource utilization (HRU), and clinical outcomes of stable post-myocardial infarction (MI) patients with and without DM.

To assess associations of health-related quality of life (HRQoL) with patient profile, resource use, cardiovascular (CV) events and mortality in stable patients post-myocardial infarction (MI).

Weather conditions affect the incidence of acute myocardial infarction (AMI). However, little is known on the association of weather temperature and humidity with AMI hospitalizations in a super-aging society. This study sought to examine this association. We included 87,911 consecutive patients with AMI admitted to Japanese acute-care hospitals between April 1, 2012 and March 31, 2015. The primary outcome was the number of AMI hospitalizations per day. Multilevel mixed-effects linear regression models were used to estimate the association of the average temperature and humidity, 1 day before hospital admission, with AMI hospitalizations, after adjusting for weather, hospital, and patient demographics.Lower temperature and humidity were associated with an increased number of AMI hospitalizations (coefficient - 0.500 [- 0.524 to - 0.474] per °C change, p < 0.001 and coefficient - 0.012 [- 0.023 to - 0.001] per % change, p = 0.039, respectively). The effects of temperature and humidity on AMI hospitalization did not differ by age and sex (all interaction p > 0.05), but differed by season. However, higher temperatures in spring (coefficient 0.089 [0.025 to 0.152] per °C change, p = 0.010) and higher humidity in autumn (coefficient 0.144 [0.121 to 0.166] per % change, p < 0.001) were risk factors for AMI hospitalization. Increased average temperatures and humidity, 1 day before hospitalization, are associated with a decreased number of AMI hospitalizations.

 Rivaroxaban monotherapy was noninferior to combination therapy (rivaroxaban plus antiplatelet therapy) in efficacy but superior in safety in the Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial. Among 2,215 patients with atrial fibrillation (AF) and stable coronary artery disease (CAD), 1,378 had baseline creatinine clearance (CrCl) ≥50 mL/min and received 10 (underdose) or 15 mg/d (standard-dose) rivaroxaban. We aimed to assess the effects of rivaroxaban underdose on clinical outcomes.

Data on the association of multimorbidity and functional impairment with cardiovascular (CV) and non-CV outcomes among older myocardial infarction (MI) patients are limited.

Atrial remodeling due to high-burden atrial fibrillation (AF) is associated with cardioembolic stroke (CES). As not all CESs is caused by AF, we analyzed the diagnostic values of each echocardiographic parameter to distinguish likely AF-related CES in acute stroke patients while in non-AF rhythm.

The current alanine aminotransferase (ALT) upper limit of normal was defined using selected healthy Caucasian blood donors. Given the global rise in obesity and different body habitus in Asians, we aimed to perform a systematic review and meta-analysis combined with bootstrap modeling and individual patient data validation to estimate the ALT upper threshold for Asians, including the overweight and diabetics. We included studies from PubMed, Embase, and Cochrane database searches that identified individuals without known liver diseases (i.e., viral hepatitis, alcohol, and ultrasound-detected nonalcoholic fatty liver disease). The mean ALT (U/L) was estimated using a random-effects mixed model and upper threshold (95th-percentile value, U/L) via a bootstrap model with 10,000 resamples. We screened 4,995 studies and identified 86 studies that reported ALT values for 526,641 individuals without excessive alcohol intake or known liver diseases, yielding a mean ALT of 19 and ALT upper threshold of 32. The ALT upper threshold was 37 in males versus 31 in females, 39 in overweight versus 28 in normal-weight individuals, and 36 for diabetics versus 33 for nondiabetics. We validated our study level data with individual patient level data in 6,058 individuals from five study centers in Japan. Consistent with our study-level data, we found that the ALT upper threshold in our individual patient data analysis was indeed higher in overweight versus normal-weight individuals (39 vs. 32) and in diabetics versus nondiabetics (42 vs. 33). Conclusion: We provide validated reference ranges for ALT upper threshold derived from Asians without known liver disease, including individuals with ultrasound-detected nonalcoholic fatty liver disease who are normal weight, overweight, nondiabetic, and diabetic, to inform practice.

Our group has conducted extensive basic and preclinical studies of the use of human induced pluripotent cell (iPSC)-derived neural stem/progenitor cell (hiPSC-NS/PC) grafts in models of spinal cord injury (SCI). Evidence from animal experiments suggests this approach is safe and effective. We are preparing to initiate a first-in-human clinical study of hiPSC-NS/PC transplantation in subacute SCI.

To evaluate a predictive model for robust estimation of daily out-of-hospital cardiac arrest (OHCA) incidence using a suite of machine learning (ML) approaches and high-resolution meteorological and chronological data.