Mucosal Fixed Drug Eruption with Oral, Conjunctival, Nasal, and Anal Lesions: A Case Report.

is missing (Short communication).

RECURRENCE RATE OF CYSTOID MACULAR EDEMA WITH TOPICAL DORZOLAMIDE TREATMENT AND ITS RISK FACTORS IN RETINITIS PIGMENTOSA.

PURPOSE: To investigate the rate of the recurrence of cystoid macular edema (CME) secondary to retinitis pigmentosa (RP) after the initiation of topical dorzolamide and the recurrence risk factors. METHODS: We retrospectively analyzed the data of RP patients at Kyushu University Hospital. We included patients who showed a treatment response to 1.0% topical dorzolamide. The day of treatment initiation was set as the baseline. Topical dorzolamide treatment was continued during the follow-up. The recurrence of CME (defined as a >20% increase in central subfield thickness compared to previous visit, or a central subfield thickness value that exceed baseline value) was evaluated at each follow-up visit. Risk factors for RP-CME recurrence were analyzed by Cox proportional hazards modeling. A Kaplan-Meier survival analysis was used to evaluate the time to recurrent RP-CME. RESULTS: Forty RP-CME patients showed a treatment response to topical dorzolamide. During the mean 3.9-year follow-up, 14 patients exhibited recurrence; its rate was 15.6%, 34.7%, and 48.7% at 1, 3, and 5 years, respectively. A high baseline central subfield thickness was significantly associated with recurrent (hazard ratio 1.11, 95% CI: 1.05-1.18, P = 0.0004). CONCLUSION: The recurrence rate of RP-CME increased with time. A high baseline central subfield thickness value was a risk factor for recurrence.

Tissue Sheet Engineered Using Human Umbilical Cord-Derived Mesenchymal Stem Cells Improves Diabetic Wound Healing.

Diabetic foot ulceration is a common chronic diabetic complication. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been widely used in regenerative medicine owing to their multipotency and easy availability. We developed poly(lactic-co-glycolic acid) (PLGA)-based scaffold to create hUC-MSC tissue sheets. In vitro immunostaining showed that hUC-MSC tissue sheets formed thick and solid tissue sheets with an abundance of extracellular matrix (ECM). Diabetic wounds in mice treated with or without either the hUC-MSC tissue sheet, hUC-MSC injection, or fiber only revealed that hUC-MSC tissue sheet transplantation promoted diabetic wound healing with improved re-epithelialization, collagen deposition, blood vessel formation and maturation, and alleviated inflammation compared to that observed in other groups. Taken collectively, our findings suggest that hUC-MSCs cultured on PLGA scaffolds improve diabetic wound healing, collagen deposition, and angiogenesis, and provide a novel and effective method for cell transplantation, and a promising alternative for diabetic skin wound treatment.

Heart rate response to orthostatic challenge in patients with dementia with Lewy bodies and Alzheimer's disease.

BACKGROUND: To elucidate the differences in autonomic dysfunction between dementia with Lewy bodies (DLB) and Alzheimer's disease using a simple and convenient method, we investigated the heart rate response to orthostatic challenge. METHODS: Ninety-seven people participated in this cross-sectional study, and data from 26 DLB patients, 29 Alzheimer's disease patients, and 25 healthy elderly individuals were analysed. Participants underwent postural changes, including 5 min in a supine position, 1 min in a sitting position, and 3 min in an orthostatic position. Their heart rates were continuously recorded. Two heart rate variables were analysed as main outcomes: (i) the difference between heart rate in the sitting position and the peak heart rate within 15 s of orthostasis, defined as the 'early heart rate increase'; and (ii) the difference between the peak heart rate and the negative peak heart rate after this, defined as 'early heart rate recovery.' An early heart rate increase has been considered to reflect parasympathetic and sympathetic functions. Early heart rate recovery is considered to reflect parasympathetic function. We also investigated the frequency domains of resting heart rate variability. RESULTS: A significant difference was observed across the three groups in early heart rate increase, and that of the DLB group was lower than that of the healthy control group. Early heart rate recovery also differed significantly across the three groups, and that of the DLB group was less than that of the healthy control group. In addition, the power of the low-frequency component, which represents both sympathetic and parasympathetic activity, was significantly decreased in the DLB group compared to the Alzheimer's disease group. CONCLUSIONS: Impaired heart rate response to standing was detected in patients with DLB. Electrocardiogram is a convenient, non-invasive method that might be useful as a subsidiary marker for DLB diagnosis and differentiation from Alzheimer's disease.

Plasmodium vivax liver stage assay platforms using Indian clinical isolates.

BACKGROUND: Vivax malaria is associated with significant morbidity and economic loss, and constitutes the bulk of malaria cases in large parts of Asia and South America as well as recent case reports in Africa. The widespread prevalence of vivax is a challenge to global malaria elimination programmes. Vivax malaria control is particularly challenged by existence of dormant liver stage forms that are difficult to treat and are responsible for multiple relapses, growing drug resistance to the asexual blood stages and host-genetic factors that preclude use of specific drugs like primaquine capable of targeting Plasmodium vivax liver stages. Despite an obligatory liver-stage in the Plasmodium life cycle, both the difficulty in obtaining P. vivax sporozoites and the limited availability of robust host cell models permissive to P. vivax infection are responsible for the limited knowledge of hypnozoite formation biology and relapse mechanisms, as well as the limited capability to do drug screening. Although India accounts for about half of vivax malaria cases world-wide, very little is known about the vivax liver stage forms in the context of Indian clinical isolates. METHODS: To address this, methods were established to obtain infective P. vivax sporozoites from an endemic region in India and multiple assay platforms set up to detect and characterize vivax liver stage forms. Different hepatoma cell lines, including the widely used HCO4 cells, primary human hepatocytes as well as hepatocytes obtained from iPSC's generated from vivax patients and healthy donors were tested for infectivity with P. vivax sporozoites. RESULTS: Both large and small forms of vivax liver stage are detected in these assays, although the infectivity obtained in these platforms are low. CONCLUSIONS: This study provides a proof of concept for detecting liver stage P. vivax and provide the first characterization of P. vivax liver stage forms from an endemic region in India.

Development of a novel noninvasive system for measurement and imaging of the arterial phase oxygen density ratio in the retinal microcirculation.

PURPOSE: This study was conducted in order to develop a novel noninvasive system for measurement and imaging of the arterial oxygen density ratio (ODR) in the retinal microcirculation. METHODS: We developed a system composed of two digital cameras with two different filters, which were attached to a fundus camera capable of simultaneously obtaining two images. Actual measurements were performed on healthy volunteer eyes (n = 61). A new algorithm for ODR measurement and pixel-level imaging of erythrocytes was constructed from these data. The algorithm was based on the morphological closing operation and the line convergence index filter. For system calibration, we compared and verified the ODR values in arterioles and venules that were specified in advance for 56 eyes with reproducibility. In 10 additional volunteers, ODR measurements and imaging of the arterial phase in the retinal microcirculation corresponding to changes in oxygen saturation of the peripheral arteries at normal breathing and breath holding were performed. RESULTS: Estimation of incident light to erythrocytes and pixel-level ODR calculation were achieved using the algorithm. The mean ODR values of arterioles and venules were 0.77 ± 0.060 and 1.02 ± 0.067, respectively. It was possible to separate these regions, calibrate at the pixel level, and estimate the arterial phase. In each of the 10 volunteers, changes in the arterial phase ODR corresponding to changes in oxygen saturation of the peripheral arteries were observed before and after breath holding on ODR images. The mean ODR in 10 volunteers was increased by breath holding (p < 0.05). CONCLUSIONS: We developed a basic system for arterial phase ODR measurement and imaging of the retinal microcirculation. With further validation and development, this may provide a useful tool for evaluating retinal oxygen metabolism in the retinal microcirculation.

Complete regression of branching vascular network in polypoidal choroidal vasculopathy by ranibizumab and photodynamic therapy, two case reports.

BACKGROUND: Polypoidal choroidal vasculopathy (PCV) consists of polyps that potentially cause massive subretinal hemorrhage and their branching vascular network (BVN) of feeder vessels. Although conventional indocyanine green angiography (IA) has shown anti-vascular endothelial growth factor (VEGF) agents and/or photodynamic therapy (PDT) to successfully induce polyp closure, the BVN appears resistant to these therapies and serves as the origin of recurrent active polyps. Recently introduced optical coherence tomography angiography (OCT-A) enables more frequent angiographic evaluation of polyps and the BVN than does conventional IA since it does not require intravenous fluorescent dye injection and is thus considered non-invasive. CASE PRESENTATION: Case 1. A 70-year-old male with PCV in his left eye suffered from vision deterioration (20/40) due to persistent subretinal fluid despite 42 intravitreal injections of ranibizumab (IVRs) over 5 years and 7 months. PDT was performed as an adjunct therapy 3 days after the 43rd IVR. IA at 3 months after PDT showed successful polyp closure but persisting BVN. However, more frequent evaluation with OCT-A starting at 1 week after PDT demonstrated complete regression of both the BVN and polyp. OCT-A at every subsequent outpatient visit depicted gradual re-perfusion of the BVN and the restoration of most of its original network at 3 months, which was compatible with IA findings. Neither OCTA nor IA revealed polyp recurrence at 3 months. Case 2. A 65-year-old female suffering from left vision deterioration due to PCV underwent 5 intravitreal injections of aflibercept. Since her subretinal fluid persisted, the treatment was switched to a combination of IVR and PDT. OCT-A revealed marked regression of the BVN and polyp at 2 weeks, but the BVN had regained its original shape at 2 months without any sign of polyp recurrence. CONCLUSIONS: Differently from previous observations obtained by IA alone, more frequent non-invasive OCT-A examination revealed complete but transient regression of the BVN just after combination therapy with IVR and PDT.

Is prolongation of corrected QT interval associated with seizures induced by electroconvulsive therapy reduced by atropine sulfate?

BACKGROUND: Electrocardiogram abnormalities have been reported during electroconvulsive therapy (ECT). A corrected QT interval (QTc) prolongation indicates delayed ventricular repolarization, which can trigger ventricular arrhythmias such as torsade de pointes (TdP). We examined the QTc changes during generalized tonic-clonic seizures induced by ECT, and the effects of atropine sulfate on these QTc changes. METHODS: We analyzed heart rate, QT interval, and QTc in 32 patients with depression who underwent ECT (25 women, 67.4 ± 8.7 years of age). The QTc from -30 to 0 seconds prestimulation was used as baseline, which was compared with QTc at 20-30 seconds and 140-150 seconds poststimulus onset. RESULTS: QTc was significantly prolonged at 20-30 seconds poststimulus, then significantly decreased at 140-150 seconds poststimulus, compared with baseline. QTc prolongation induced by ECT was significantly decreased by atropine sulfate. CONCLUSIONS: These data suggest that the risk of TdP may be enhanced by ECT. Further, the risk of cardiac ventricular arrhythmias, including TdP, may be reduced by administration of atropine sulfate.

One-Year Outcomes following Intravitreal Aflibercept for Polypoidal Choroidal Vasculopathy in Japanese Patients: The APOLLO Study.

PURPOSE: To evaluate 1-year outcomes of intravitreal injections of aflibercept (IVA) in Japanese polypoidal choroidal vasculopathy (PCV) patients. METHODS: In this prospective, open-label, single-arm multicenter clinical trial, treatment-naïve PCV patients received IVA (2.0 mg) every 2 months, after 3 initial monthly doses. The primary endpoint assessed was the proportion of patients maintaining baseline best-corrected visual acuity (BCVA) at 1 year. RESULTS: Fifty eyes with PCV were included in the study. BCVA was maintained or improved in 97.6% of the patients. Mean logMAR BCVA at baseline was 0.33, and had improved to 0.12 logMAR 1 year after the initiation of aflibercept treatment (p < 0.001). Mean central foveal thickness decreased from 356 to 239 µm (p < 0.001). Complete regression of polypoidal lesions was seen in 72.5% after 1 year of treatment. CONCLUSIONS: One year of IVA resulted in stabilization of BCVA and anatomical improvement in Japanese PCV patients.

Effect of Exercise Training on Red Blood Cell Distribution Width as a Marker of Impaired Exercise Tolerance in Patients With Coronary Artery Disease.

Red blood cell distribution width (RDW) can predict mortality in cardiovascular disease. However, the underlying mechanisms of the beneficial prognostic marker remain unknown. The purpose of this study was to investigate whether the RDW is related to impaired exercise tolerance and exercise training (ET) effect on RDW in patients with coronary artery disease (CAD).Seventy-eight patients who underwent ET by supervised bicycle ergometer during 3 weeks served as the ET group whereas 30 patients who did not undergo ET were the control group. Exercise stress test with cardiopulmonary analysis was performed in the ET group. Peak oxygen uptake (from 14.1 ± 4.0 to 15.1 ± 3.8 mL/kg/minute, P < 0.05) significantly increased in the ET group. Although RDW and serum erythropoietin concentration (EP) before the observation period did not differ between the ET and control groups, RDW (from 44.4 ± 4.7 to 43.4 ± 3.8 fL, P < 0.01) and EP (from 27.9 ± 15.8 to 22.9 ± 8.2 mIU/mL, P < 0.005) significantly decreased in the ET group, however, these parameters did not change in the control group. In the ET group, RDW was negatively correlated with peak oxygen uptake (r = -0.55, P < 0.01) and the changes in RDW before and after ET were positively correlated with the changes in EP (r = 0.39, P < 0.005).Thus, ET increases exercise tolerance and decreases RDW in association with increased oxygen uptake in patients with CAD.

Factors affecting visual acuity after cataract surgery in patients with retinitis pigmentosa.

PURPOSE: To investigate the factors affecting visual acuity after cataract surgery in patients with retinitis pigmentosa (RP). DESIGN: Retrospective, observational study. PARTICIPANTS: We retrospectively reviewed the charts of a consecutive series of 40 patients with RP who underwent cataract surgery. METHODS: The changes in preoperative and postoperative best-corrected visual acuity (BCVA) were measured. We investigated the relation between preoperative mean deviation (MD) value on the Humphrey Field Analyzer (HFA: the central 10-2 program; Humphrey Instruments, Inc, San Leandro, CA) and final BCVA. We also investigated the relationship between preoperative ellipsoid zone (EZ; also called the inner/outer segment junction) conditions and final BCVA. In addition, we showed the prevalence of macular complications and capsule complications. MAIN OUTCOME MEASURES: The BCVA, slit-lamp biomicroscopic analysis, visual field, and optical coherence tomography (OCT) were obtained. RESULTS: The mean of the BCVA significantly improved after cataract surgery from 0.76 (range, -0.08 to 2.30) to 0.45 (range, -0.18 to 2.00) (P < 0.005). However, final BCVA did not improve in 30 eyes (53.6%). The preoperative MD value and the final BCVA were significantly correlated, and the final BCVA significantly improved in the less advanced RP group (MD was ≥-15 decibels [dB]). The final BCVA was significantly better in the group in which preoperative OCT showed a normal EZ than in the groups in which the EZ was abnormal or not visible. Posterior capsular opacification was observed in 47 eyes (83.9%), and 23 eyes (41.1%) underwent YAG laser capsulotomy within a mean follow-up time of 3 years. CONCLUSIONS: Final BCVA in approximately half of the eyes improved after cataract surgery in patients with RP. The preoperative ophthalmic examinations that may reflect macular (or foveal) function, such as HFA 10-2 program and OCT, are important parameters to assess postoperative visual outcome.

A Triphasic Change of Cardiac Autonomic Nervous System During Electroconvulsive Therapy.

OBJECTIVES: Dynamic autonomic activity changes have been repeatedly reported during electroconvulsive therapy (ECT). However, the specific timing of these changes remains unclear. To clarify whether sympathetic or parasympathetic nervous activity contributes separately to the second stage and the third stage during and after induced seizures by ECT, we examined heart rate (HR) and spectral analysis of variability (HRV) during ECT. METHODS: Seventeen patients with depression participated in the study and underwent ECT. The R-R intervals (RRI) were recorded and analyzed sequentially for the HRV indices high-frequency (HF) (an index of parasympathetic activity) and low-frequency (LF)/high-frequency (an index of sympathetic activity) for 4 minutes before and after stimulus onset by the maximum entropy method. Averaged HRs were compared between 3 heart beats prestimulus and poststimulus onset. The HRV power in the range of 30 to 80 and 80 to 130 seconds after a seizure was compared between the HF and LF/HF components. RESULTS: There was a significant reduction of the averaged HR over 3 HRs just after stimulus onset, suggesting parasympathetic dominance in the first phase. The LF/HF power significantly increased in the 30 to 80 s range after stimulus onset, whereas the HF power significantly increased in the 80 to 130 s range after stimulus onset, reflecting sympathetic activation in the second phase and parasympathetic activation in the third phase, respectively. CONCLUSIONS: The evaluation of HR and HRV revealed a triphasic change from parasympathetic to sympathetic to parasympathetic cardiac autonomic activity after ECT stimulus onset in depression patients.

Survey on Findings and Utilization of Preoperative Chest Radiography in Ophthalmic Surgery.

Objective: The objective of this paper is to reconsider the significance of preoperative chest radiography (CXR) before ophthalmic surgery through investigation of imaging findings and usage status. Methods: This retrospective observational clinical study involved 1616 patients who underwent ophthalmic surgery at Saga University Hospital from 1 January 2019 to 31 December 2020. The patients' radiology reports were obtained from the electronic medical records, and their CXR findings, therapeutic interventions, and progress were investigated. Results: Among all patients, 539 (33.4%) had abnormal preoperative CXR findings. Of these patients, 74 (4.6%) had newly identified abnormal findings. In both patient groups, approximately 70% of patients with abnormal findings were aged ≥70 years, and interstitial shadows were the most common finding. Among all patients with abnormal findings, three (0.19%) received preoperative therapeutic interventions, and all surgeries were performed safely. Forty-three patients with abnormal findings were referred to our hospital or other hospitals for further investigation and treatment postoperatively. Among those patients, eight (0.5%) had primary lung cancer, seven underwent surgery, and one received chemoradiation. The other patients were also followed up and received appropriate therapeutic interventions. Conclusions: Before ophthalmic surgery, few patients required actual therapeutic interventions based on their CXR results. However, many abnormal findings were revealed in elderly patients, including some serious diseases. Furthermore, research has suggested that appropriate therapeutic intervention after ophthalmologic surgery may reduce the risk of a poor life prognosis. This study clearly shows that preoperative CXR is not only useful for perioperative systemic management but also ultimately benefits patients. It is also considered particularly meaningful for patients aged ≥70 years.

Human induced pluripotent stem cell-derived closed-loop cardiac tissue for drug assessment.

Human iPSC-derived cardiomyocytes (hiPSC-CMs) exhibit functional immaturity, potentially impacting their suitability for assessing drug proarrhythmic potential. We previously devised a traveling wave (TW) system to promote maturation in 3D cardiac tissue. To align with current drug assessment paradigms (CiPA and JiCSA), necessitating a 2D monolayer cardiac tissue, we integrated the TW system with a multi-electrode array. This gave rise to a hiPSC-derived closed-loop cardiac tissue (iCT), enabling spontaneous TW initiation and swift pacing of cardiomyocytes from various cell lines. The TW-paced cardiomyocytes demonstrated heightened sarcomeric and functional maturation, exhibiting enhanced response to isoproterenol. Moreover, these cells showcased diminished sensitivity to verapamil and maintained low arrhythmia rates with ranolazine-two drugs associated with a low risk of torsades de pointes (TdP). Notably, the TW group displayed increased arrhythmia rates with high and intermediate risk TdP drugs (quinidine and pimozide), underscoring the potential utility of this system in drug assessment applications.

MutT homolog-1 attenuates oxidative DNA damage and delays photoreceptor cell death in inherited retinal degeneration.

Retinitis pigmentosa (RP) is a genetically heterogenous group of inherited retinal degenerative diseases resulting from photoreceptor cell death and affecting >1 million persons globally. Although oxidative stress has been implicated in the pathogenesis of RP, the mechanisms by which oxidative stress mediates photoreceptor cell death are largely unknown. Here, we show that oxidation of nucleic acids is a key component in the initiation of death-signaling pathways in rd10 mice, a model of RP. Accumulation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) increased in photoreceptor cells, and especially within their nuclei, in rd10 mice as well as in Royal College of Surgeons rats, another model of RP caused by different genetic mutations. Vitreous samples from humans with RP contained higher levels of 8-oxo-dG excreted than samples from nondegenerative controls. Transgenic overexpression of human MutT homolog-1, which hydrolyzes oxidized purine nucleoside triphosphates in the nucleotide pool, significantly attenuated 8-oxo-dG accumulation in nuclear DNA and photoreceptor cell death in rd10 mice, in addition to suppressing DNA single-strand break formation, poly(ADP-ribose) polymerase activation, and nuclear translocation of apoptosis-inducing factor. These findings indicate that oxidative DNA damage is an important process for the triggering of photoreceptor cell death in rd10 mice and suggest that stimulation of DNA repair enzymes may be a novel therapeutic approach to attenuate photoreceptor cell loss in RP.

Clinical evidence of sustained chronic inflammatory reaction in retinitis pigmentosa.

PURPOSE: To study the nature of inflammatory reaction in eyes of patients with retinitis pigmentosa (RP) and its possible role in the pathogenesis of RP. DESIGN: Retrospective, observational study. PARTICIPANTS AND CONTROLS: Three hundred seventy-one consecutive patients diagnosed with typical RP were included in this study. We included 165 patients without active inflammatory diseases, including 20 patients diagnosed with cataract, and 36 patients diagnosed with idiopathic epiretinal membrane as controls. METHODS: Density of the inflammatory cells in the anterior vitreous cavity was measured and graded by slit-lamp biomicroscopy. A multiplex enzyme-linked immunosorbent assay (ELISA) was performed to evaluate the concentration of cytokines and chemokines in aqueous humor and vitreous fluid of patients with RP and controls. In addition, we investigated the relationship between visual function and anterior vitreous cells in these patients. MAIN OUTCOME MEASURES: Slit-lamp biomicroscopic analysis, best-corrected visual acuity, visual field analysis, and multiplex ELISA. RESULTS: In 190 of 509 eyes with RP (37.3%), "1+" (5-9 cells per field) or more cells were observed in the anterior vitreous cavity. Strong inflammatory reaction with "2+" cells (10-30 cells per field) was associated with younger age. In the elderly patients with RP, significantly decreased visual function was seen in a group with "1+" or more cells (P<0.05). Moreover, the levels of a variety of proinflammatory cytokines and chemokines, including monocyte chemotactic protein-1, were increased both in the aqueous humor and vitreous fluid of RP patients compared with the levels in control patients. CONCLUSIONS: Sustained chronic inflammatory reaction may underlie the pathogenesis of RP, suggesting interventions for ocular inflammatory reaction as a potential treatment for patients with RP. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Laboratory evidence of sustained chronic inflammatory reaction in retinitis pigmentosa.

PURPOSE: To study the nature of retinal inflammatory response in rd10 mice, an animal model of retinitis pigmentosa (RP), and to investigate the effect of an antioxidant on retinal inflammation and photoreceptor apoptosis. DESIGN: Experimental study. PARTICIPANTS AND CONTROLS: This study included 42 untreated rd10 mice, 30 N-acetylcysteine (NAC)-treated rd10 mice, and 20 C57BL/6 mice as controls. METHODS: Real-time polymerase chain reaction (PCR) was performed to evaluate the expression levels of inflammatory factors (proinflammatory cytokines and chemokines) in rd10 mouse retinas. Rd10 mice were treated with an antioxidant NAC, and its effect on retinal inflammation and photoreceptor apoptosis were examined by immunohistochemistry. MAIN OUTCOME MEASURES: Real-time PCR and immunohistochemistry. RESULTS: We demonstrated sequential events involving increased expression of proinflammatory cytokines and chemokines, activation of microglia, and photoreceptor apoptosis during retinal degeneration of rd10 mice. Furthermore, antioxidant treatment with NAC prevented the photoreceptor cell death along with suppression of inflammatory factors and microglial activation. CONCLUSIONS: Sustained chronic inflammatory reaction may contribute to the pathogenesis of retinal degeneration in rd10 mice, suggesting interventions for ocular inflammatory reaction using antioxidants as a potential treatment for patients with RP. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Development of a thick and functional human adipose-derived stem cell tissue sheet for myocardial infarction repair in rat hearts.

BACKGROUND: Heart failure (HF) is a major cause of death worldwide. The most effective treatment for HF is heart transplantation, but its use is limited by the scarcity of donor hearts. Recently, stem cell-based therapy has emerged as a promising approach for treating myocardial infarction. Our research group has been investigating the use of human induced pluripotent stem cell-derived cardiomyocyte patches as a potential therapeutic candidate. We have successfully conducted eight cases of clinical trials and demonstrated the safety and effectiveness of this approach. However, further advancements are necessary to overcome immune rejection and enhance therapeutic efficacy. In this study, we propose a novel and efficient technique for constructing mesenchymal stem cell (MSC) tissue sheets, which can be transplanted effectively for treating myocardial infarction repair. METHODS: We applied a one-step method to construct the human adipose-derived mesenchymal stem cell (hADSC) tissue sheet on a poly(lactic-co-glycolic acid) fiber scaffold. Histology, immunofluorescence, and paracrine profile assessment were used to determine the organization and function of the hADSC tissue sheet. Echocardiography and pathological analyses of heart sections were performed to evaluate cardiac function, fibrosis area, angiogenesis, and left ventricular remodeling. RESULTS: In vitro, the hADSC tissue sheet showed great organization, abundant ECM expression, and increased paracrine secretion than single cells. In vivo, the hADSC tissue sheet group demonstrated improved cardiac functional recovery, less ventricular remodeling, decreased fibrosis, and enhanced angiogenesis than the MI group. CONCLUSIONS: We developed thick and functional hADSC tissue sheets via the one-step strategy. The hADSC tissue sheet showed excellent performance in treating myocardial infarction in the rat model.

ONO-1301 enhances post-transplantation survival of human induced pluripotent stem cell-derived cardiac tissue sheet by promoting angiogenesis.

BACKGROUND: Transplanting human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) tissue sheets effectively treat ischemic cardiomyopathy. Cardiac functional recovery relies on graft survival in which angiogenesis played an important part. ONO-1301 is a synthetic prostacyclin analog with proangiogenic effects. We hypothesized that transplantation of hiPSC-CM tissue sheets with slow-release ONO-1301 scaffold could promote hostgraft angiogenesis, enhance tissue survival and therapeutic effect. METHODS: We developed hiPSC-CM tissue sheets with ONO-1301 slow-release scaffold and evaluated their morphology, gene expression, and effects on angiogenesis. Three tissue sheet layers were transplanted into a rat myocardial infarction (MI) model. Left ventricular ejection fraction, gene expression in the MI border zone, and angiogenesis effects were investigated 4 weeks after transplantation. RESULTS: In vitro assessment confirmed the slow-release of ONO-1301, and its pro-angiogenesis effects. In addition, in vivo data demonstrated that ONO-1301 administration positively correlated with graft survival. Cardiac tissue as thick as ∼900 µm was retained in the ONO (+) treated group. Additionally, left ventricular ejection fraction of the ONO (+) group was significantly enhanced, compared to ONO (-) group. The ONO (+) group also showed significantly improved interstitial fibrosis, higher capillary density, increased number of mature blood vessels, along with an enhanced supply of oxygen, and nutrients. CONCLUSIONS: Slow-release ONO-1301 scaffold provided an efficient delivery method for thick hiPSC-CM tissue. ONO-1301 promotes angiogenesis between the host and graft and improves nutritional and oxygen supply, thereby enhancing the survival of transplanted cells, effectively improving ejection fraction, and therapeutic effects.