It has been nearly 15 years since the discovery of human-induced pluripotent stem cells (iPSCs). During this time, differentiation methods to targeted cells have dramatically improved, and many types ...of cells in the human body can be currently generated at high efficiency. In the cardiovascular field, the ability to generate human cardiomyocytes in vitro with the same genetic background as patients has provided a great opportunity to investigate human cardiovascular diseases at the cellular level to clarify the molecular mechanisms underlying the diseases and discover potential therapeutics. Additionally, iPSC-derived cardiomyocytes have provided a powerful platform to study drug-induced cardiotoxicity and identify patients at high risk for the cardiotoxicity; thus, accelerating personalized precision medicine. Moreover, iPSC-derived cardiomyocytes can be sources for cardiac cell therapy. Here, we review these achievements and discuss potential improvements for the future application of iPSC technology in cardiovascular diseases.
Abstract
Compact cardiomyocytes that make up the ventricular wall of the adult heart represent an important therapeutic target population for modeling and treating cardiovascular diseases. Here, we ...established a differentiation strategy that promotes the specification, proliferation and maturation of compact ventricular cardiomyocytes from human pluripotent stem cells (hPSCs). The cardiomyocytes generated under these conditions display the ability to use fatty acids as an energy source, a high mitochondrial mass, well-defined sarcomere structures and enhanced contraction force. These ventricular cells undergo metabolic changes indicative of those associated with heart failure when challenged in vitro with pathological stimuli and were found to generate grafts consisting of more mature cells than those derived from immature cardiomyocytes following transplantation into infarcted rat hearts. hPSC-derived atrial cardiomyocytes also responded to the maturation cues identified in this study, indicating that the approach is broadly applicable to different subtypes of the heart. Collectively, these findings highlight the power of recapitulating key aspects of embryonic and postnatal development for generating therapeutically relevant cell types from hPSCs.
Cardiac fibroblasts play an essential role in the development of the heart and are implicated in disease progression in the context of fibrosis and regeneration. Here, we establish a simple organoid ...culture platform using human pluripotent stem cell-derived epicardial cells and ventricular cardiomyocytes to study the development, maturation, and heterogeneity of cardiac fibroblasts under normal conditions and following treatment with pathological stimuli. We demonstrate that this system models the early interactions between epicardial cells and cardiomyocytes to generate a population of fibroblasts that recapitulates many aspects of fibroblast behavior in vivo, including changes associated with maturation and in response to pathological stimuli associated with cardiac injury. Using single cell transcriptomics, we show that the hPSC-derived organoid fibroblast population displays a high degree of heterogeneity that approximates the heterogeneity of populations in both the normal and diseased human heart. Additionally, we identify a unique subpopulation of fibroblasts possessing reparative features previously characterized in the hearts of model organisms. Taken together, our system recapitulates many aspects of human cardiac fibroblast specification, development, and maturation, providing a platform to investigate the role of these cells in human cardiovascular development and disease.
Transplant of human induced pluripotent stem cell derived cardiomyocytes (hiPS-CMs) cell-sheet is a promising approach for treating ischemic cardiomyopathy (ICM). However, poor blood supply to the ...transplanted cell-sheet is a concern related to the effectiveness and durability of the treatment. Herein, we hypothesized that the combined the omentum flap might enhance survival and the therapeutic effects of hiPS-CM cell-sheet transplant for ICM treatment. Treatment by Wnt signaling molecules in hiPS cells produced hiPS-CMs, which were magnetically labeled by superparamagnetic iron oxide (SPIO), followed by culture in the thermoresponsive dishes to generate hiPS-CMs cell-sheets. A porcine ICM model included 4 groups; sham operation, omentum flap only, cell-sheet only, or combination therapy. Ejection fraction (EF) was significantly greater in the cell-sheet only and combination group compared to the other groups during the follow-up period. At 3 months, the EF of the combination group was significantly greater than that of the cell-sheet only group. Consistently, the survival rate of the SPIO-labeled hiPS-CMs, as assessed by MRI, was significantly greater in the combination group than in the cell-sheet only group. This cell delivery system would be useful in optimizing the hiPS-CM cell-sheet transplant for treating severe heart failure.
Human pluripotent stem cell-derived cardiomyocytes (CMs) are a promising tool for cardiac cell therapy. Although transplantation of induced pluripotent stem cell (iPSC)-derived CMs have been reported ...in several animal models, the treatment effect was limited, probably due to poor optimization of the injected cells. To optimize graft cells for cardiac reconstruction, we compared the engraftment efficiency of intramyocardially-injected undifferentiated-iPSCs, day 4 mesodermal cells, and day 8, day 20, and day 30 purified iPSC-CMs after initial differentiation by tracing the engraftment ratio (ER) using in vivo bioluminescence imaging. This analysis revealed the ER of day 20 CMs was significantly higher compared to other cells. Transplantation of day 20 CMs into the infarcted hearts of immunodeficient mice showed good engraftment, and echocardiography showed significant functional improvement by cell therapy. Moreover, the imaging signal and ratio of Ki67-positive CMs at 3 months post injection indicated engrafted CMs proliferated in the host heart. Although this graft growth reached a plateau at 3 months, histological analysis confirmed progressive maturation from 3 to 6 months. These results suggested that day 20 CMs had very high engraftment, proliferation, and therapeutic potential in host mouse hearts. They also demonstrate this model can be used to track the fate of transplanted cells over a long time.
Isolation of specific cell types, including pluripotent stem cell (PSC)-derived populations, is frequently accomplished using cell surface antigens expressed by the cells of interest. However, ...specific antigens for many cell types have not been identified, making their isolation difficult. Here, we describe an efficient method for purifying cells based on endogenous miRNA activity. We designed synthetic mRNAs encoding a fluorescent protein tagged with sequences targeted by miRNAs expressed by the cells of interest. These miRNA switches control their translation levels by sensing miRNA activities. Several miRNA switches (miR-1-, miR-208a-, and miR-499a-5p-switches) efficiently purified cardiomyocytes differentiated from human PSCs, and switches encoding the apoptosis inducer Bim enriched for cardiomyocytes without cell sorting. This approach is generally applicable, as miR-126-, miR-122-5p-, and miR-375-switches purified endothelial cells, hepatocytes, and insulin-producing cells differentiated from hPSCs, respectively. Thus, miRNA switches can purify cell populations for which other isolation strategies are unavailable.
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•Synthetic miRNA switches can purify target cell populations based on miRNA activity•miR-1-, -208a-, and -499a-5p-switches highly purify hPSC-derived cardiomyocytes•miR-Bim switches enrich for cardiomyocytes without the need for cell sorting•miRNA switches can isolate desired cell types without significant side effects
Miki et al. develop synthetic miRNA switches for isolating cell populations that are otherwise difficult to purify. Several miRNA-responsive switches precisely and efficiently isolate human pluripotent stem cell (hPSC)-derived cardiomyocytes, and miRNA switches can be programmed for purification of various cell types including hPSC-derived endothelial cells, hepatocytes, and insulin-producing cells.
Background
Although several risk factors for chronic kidney disease (CKD) have been proposed, it remains unclear whether elevated serum uric acid (SUA) is negatively association with kidney function. ...The aim of this study was to elucidate the association between SUA and new onset and progression of CKD in a Japanese general population.
Methods
This was a population-based retrospective cohort study using annual health checkup data of residents of Iki Island. A total of 5,507 adults (979 with CKD and 4,528 without) were included. The outcomes were new onset of CKD among participants without CKD at baseline, and progression of CKD among those with CKD. A Cox proportional hazards model was used to evaluate the association between SUA and new onset and progression of CKD.
Results
During mean follow-up of 4.6 years, 757 cases of new onset of CKD and 193 with progression of CKD were observed. SUA was significantly associated with new onset of CKD (adjusted hazard ratio 1.13, 95% confidence interval 1.03–1.24 per standard deviation SD increase in SUA). In contrast, SUA was not significantly associated with progression of CKD (hazard ratio 1.08, 0.92–1.27 per SD increase). Similar results were obtained when classifying uric acid as categorical.
Conclusion
SUA was significantly associated with increased risk for new onset of CKD, but not with progression of CKD among a Japanese general population.
Little is known about the optimal daily magnesium (Mg) intake for individuals with high levels of physical activity. The aim of this study was to clarify the optimal dietary Mg intake for people with ...high levels of physical activity in a scoping review. In this review, we searched MEDLINE and Japan Medical Abstracts Society for studies published up to May 31, 2020. We conducted two searches, one for studies using gold standard measurement methods such as the balance method and factorial calculation (Search 1), and the other for studies using estimation from daily food intake (Search 2). We also performed a meta-analysis of studies that compared the Mg intake among physically active people with the Mg intake among controls. After the primary and secondary screening, 31 studies were included in the final review. All of the included studies examined professional or recreational athletes. We found no studies that examined the optimal intake of Mg using gold standard measurement methods. The Mg intake among physically active individuals was below the recommended dietary allowance in most studies. In five studies that conducted meta-analyses, physically active individuals had significantly higher intakes of Mg than controls, although these levels were still below the recommended dietary allowance. The present review revealed that evidence regarding the optimal daily magnesium intake is currently scarce, and further studies are needed.
This study aimed to clarify the relationship between the white blood cell (WBC) count and hypertension in the general Japanese population.
We conducted a population-based retrospective cohort study ...using annual health check-up data of residents of Iki City, Nagasaki Prefecture, Japan. A total of 2935 participants without hypertension at baseline were included in the present analysis. WBC counts were classified as tertile 1 (<4700/μL), tertile 2 (4700-5999/μL), and tertile 3 (≥6000/μL). The outcome was incident hypertension (blood pressure ≥140 mmHg). Multivariable-adjusted hazard ratios and 95% confidence intervals (95% CIs) were estimated using the Cox proportional hazards model.
During an average follow-up of 4.5 years, 908 participants developed hypertension. The incidence (per 100 person-years) of hypertension increased with an elevation in the WBC count (6.3 in tertile 1, 7.0 in tertile 2, and 7.4 in tertile 3). This association was significant, even after adjustment for other risk factors, including age, sex, current smoking habits, current alcohol intake, exercise habits, obesity, elevated blood pressure, diabetes mellitus, and dyslipidemia. The hazard ratios were 1.07 for tertile 2 (95% CI 0.90-1.26) and 1.27 for tertile 3 (95% CI 1.06-1.51) compared with the reference group of tertile 1 (p = 0.009).
The WBC count was associated with future development of hypertension in the general Japanese population.
The aim of this study was to investigate the association between pulse pressure (PP) and chronic kidney disease (CKD) progression among the general population in Japan. We conducted a ...population-based cohort study of the residents of Iki Island, Nagasaki, Japan, from 2008 to 2018. We identified 1042 participants who had CKD (estimated glomerular filtration rate(eGFR) < 60 mL/min/1.73 m
or the presence of proteinuria) at baseline. Cox's proportional hazard model was used to evaluate the association between PP and progression of CKD. During a 4.66-year mean follow-up, there were 241 cases of CKD progression (incident rate: 49.8 per 1000 person-years). A significant increase existed in CKD progression per 10 mmHg of PP elevation, even when adjusted for confounding factors adjusted hazard ratio 1.17 (1.06-1.29) p < 0.001. Similar results were obtained even after dividing PP into quartiles Q2: 1.14 (0.74-1.76), Q3: 1.35 (0.88-2.06), Q4: 1.87 (1.23-2.83) p = 0.003 for trend. This trend did not change significantly irrespective of baseline systolic or diastolic blood pressures. PP remained a potential predictive marker, especially for eGFR decline. In conclusion, we found a significant association between PP and CKD progression. PP might be a potential predictive marker for CKD progression.
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