A neural circuit mechanism for mechanosensory feedback control of ingestion.

Mechanosensory feedback from the digestive tract to the brain is critical for limiting excessive food and water intake, but the underlying gut-brain communication pathways and mechanisms remain poorly understood1-12. Here we show that, in mice, neurons in the parabrachial nucleus that express the prodynorphin gene (hereafter, PBPdyn neurons) monitor the intake of both fluids and solids, using mechanosensory signals that arise from the upper digestive tract. Most individual PBPdyn neurons are activated by ingestion as well as the stimulation of the mouth and stomach, which indicates the representation of integrated sensory signals across distinct parts of the digestive tract. PBPdyn neurons are anatomically connected to the digestive periphery via cranial and spinal pathways; we show that, among these pathways, the vagus nerve conveys stomach-distension signals to PBPdyn neurons. Upon receipt of these signals, these neurons produce aversive and sustained appetite-suppressing signals, which discourages the initiation of feeding and drinking (fully recapitulating the symptoms of gastric distension) in part via signalling to the paraventricular hypothalamus. By contrast, inhibiting the same population of PBPdyn neurons induces overconsumption only if a drive for ingestion exists, which confirms that these neurons mediate negative feedback signalling. Our findings reveal a neural mechanism that underlies the mechanosensory monitoring of ingestion and negative feedback control of intake behaviours upon distension of the digestive tract.

Linker Encouraged Solid State Synthesis of MOF Derived Z-Scheme NiCo2O4/NiO/C toward Efficient Removal of Organic and Inorganic Pollutants from Water.

Here, we represent a solid-state route for the construction of MOF derived multifunctional Z-scheme NiCo2O4/NiO/C applied for the photocatalytic removal of methylene blue (dye) and tetracycline (drug) and the reduction of Cr(VI) (heavy metal). The developed solid-state method yielded a highly effective NiCo2O4/NiO/C catalyst by mechanically grinding independently produced Ni and Co-MOFs and subsequently pyrolyzing them. The use of different linkers in the Ni MOF (H3-BTC linker) and Co-MOF (2-methylimidazole linker) proved to be effective in constructing the NiCo2O4/NiO/C composite, ensuring a nonaggregated distribution on a carbon framework. Such a synthesized Z-scheme NiCo2O4/NiO/C composite has performed exceptionally well to achieve excellent degradation of MB (98.23% in 120 min) and TC (92.85% in 25 min) and Cr(VI) reduction (98.22% in 20 min), with excellent recyclability and stability. The NiCo2O4/NiO/C composite, synthesized using Ni and Co-MOFs prepared with different linkers, outperformed its counterpart prepared using Ni and Co-MOFs with identical linkers (either 2-methylimidazole or H3BTC). This study paves the way for the future synthesis of MOF derived bimetallic composites for photocatalytic applications.

Plasma apixaban concentrations and thrombin generation assay parameters in response to dose reduction for atrial fibrillation.

AIMS: To investigate plasma apixaban concentrations and thrombin generation assay (TGA) parameters across different apixaban doses in atrial fibrillation patients who had dose-reduction criteria for apixaban. METHODS: This observational study included 374 patients (mean age 75.6 ± 7.7 years, 54.8% female) with dose-reduction criteria for apixaban. The patients were divided into 3 groups: (i) on-label standard dose (5 mg twice daily, n = 166); (ii) on-label reduced dose (2.5 mg twice daily, n = 55); and (iii) off-label underdose (2.5 mg twice daily, n = 153). Apixaban concentrations determined via the anti-Xa assay and TGA parameters were compared at trough levels. RESULTS: The off-label underdose group exhibited significantly lower apixaban trough concentrations than the on-label reduced-dose and standard-dose groups (56.7 ± 42.9 vs. 83.7 ± 70.4 vs. 129.9 ± 101.8 ng/mL, all P < .001). Less than 70% of all patients fell within the expected range of apixaban concentrations. Proportions exceeding the upper limit of the expected range were significantly lower in the off-label underdose group (1.3%) than in the on-label reduced-dose (9.1%, P = .005) and standard-dose (12.7%, P < .001) groups. The TGA parameters showed the on-label standard-dose group displaying the lowest thrombogenic profiles. Lower creatinine clearance was the most significant predictor of higher apixaban concentrations. CONCLUSION: Off-label underdosed apixaban resulted in lower apixaban concentrations than both on-label standard and reduced-dose regimens. A considerable proportion of the patients exhibited apixaban concentrations outside the expected range, suggesting the potential benefits of plasma concentration monitoring. Further studies are needed to compare dosages directly, investigate the impact of plasma apixaban concentration monitoring and validate the current dose-reduction criteria.

Comparative analysis of adverse drug reactions associated with new antiseizure medications from the Korea Adverse Event Reporting System database.

OBJECTIVE: This study aimed to compare and characterize the safety profiles of new antiseizure medications (ASMs) using a nationwide pharmacovigilance database from a long-term perspective in Korea. METHODS: We reviewed adverse event reports from the Korea Adverse Event Reporting System database between January 2013 and December 2022 for descriptive analysis of six new ASMs (lacosamide, levetiracetam, lamotrigine, oxcarbazepine, topiramate, and zonisamide). We investigated the frequency and characteristics of adverse drug reactions (ADRs) based on the MedDRA terminology, system organ classes, and modified WHO classification. RESULTS: We identified 5,733 reported cases of ADRs. The commonly reported ADRs associated with total ASMs were rash/urticaria (1,822, 31.8 %), dizziness (409, 7.1 %), somnolence/drowsiness (311, 5.4 %), and hepatotoxic effects (273, 4.8 %). Type B (idiosyncratic) effects (2,932; 51.1 %) were more commonly reported than Type A (related to known drug mechanisms) effects (2,613; 45.6 %). Skin and subcutaneous tissue disorders and type B effects were most commonly reported for lamotrigine and oxcarbazepine, whereas nervous system disorders and type A effects were most commonly reported for lacosamide, topiramate, and zonisamide. The pediatric group (<18 years) exhibited skin and subcutaneous tissue disorders and type B effects relatively more frequently than the adult and older adult groups. CONCLUSION: Hypersensitivity skin reactions and type B effects remained significant ADRs in the new ASMs; however, type A effects were more commonly reported in some ASMs. The pediatric group showed a higher rate of type B effects. Overall, new ASMs should also be used with caution.

Mutational analysis of pig tissue factor pathway inhibitor α to increase anti-coagulation activity in pig-to-human xenotransplantation.

Blood coagulation mediated by pig tissue factor (TF), which is expressed in pig tissues, causes an instant blood-mediated inflammatory reaction during pig-to-human xenotransplantation. Previously, we generated a soluble pig tissue factor pathway inhibitor α fusion immunoglobulin (TFPI-Ig) which inhibits pig TF activity more efficiently than human TFPI-Ig in human plasma. In this study, we generated several pig TFPI-Ig mutants and tested the efficacy of these mutants in preventing pig-to-human xenogeneic blood coagulation. Structurally important amino acid residues of pig TFPI-Ig were changed into different residues by site-directed mutagenesis. Subsequently, a retroviral vector encoding each cDNA of several pig TFPI-Ig mutants was cloned and transduced into CHO-K1 cells. After establishing stable cell lines expressing each of the pig TFPI-Ig mutants, soluble proteins were produced and purified for evaluating their inhibitory effects on pig TF-mediated blood coagulation in human plasma. The replacement of K36 and K257 with R36 and H257, respectively, in pig TFPI-Ig more efficiently blocked pig TF activity in human plasma when compared with the wild-type pig TFPI-Ig. These results may provide additional information to understand the structure of pig TFPIα, and an improved pig TFPI-Ig variant that more efficiently blocks pig TF-mediated blood coagulation during pig-to-human xenotransplantation.

Medial Rectus Disinsertion for the Management of Large-Angle Sensory Esotropia.

Background and Objectives: The aim of the report is to report the outcomes of the medial rectus (MR) disinsertion procedure for the management of large-angle esotropia (ET) patients. Materials and Methods: This is a retrospective case series of patients with large-angle ET who underwent an MR disinsertion procedure between March 2012 to April 2022. The procedure happened accidentally during muscle surgery. The demographic and clinical data, including sex, age, visual acuity, pre- and postoperative angle of strabismus, duction limitations, results of intraoperative forced duction tests, and follow-up duration were collected from medical records. Results: Five patients were enrolled in this study. The mean age was 62.2 ± 9.8 years, and the mean follow-up was 24.8 ± 8.7 months. The ET at the primary position of gaze was 92.0 ± 17.9 prism diopters (PD) before MR disinsertion and 38.0 ± 29.5 PD after MR disinsertion only. Abduction deficiency was -4 before after MR disinsertion, which improved to -1 at the last follow-up. Conclusions: The results of MR disinsertion were not as frustrating as anticipated. MR disinsertion may be considered in patients with large-angle sensory ET who refuse surgery on the opposite eye.

Epileptic seizures associated with progressive multifocal leukoencephalopathy in HIV-infected patients in Korea.

We investigated the incidence and risk factors of seizures related to progressive multifocal leukoencephalopathy (PML) in Korean patients infected with HIV. Of the 34 patients, 14 (41.2%) developed epileptic seizures during a median follow-up of 82 months. The median time from PML diagnosis to seizure onset was 44 months, ranging from 0 to 133 months. Patients with PML who developed seizures more commonly had cognitive impairment and multiple or diffuse lesions on brain MRI. These findings highlight the increased seizure risk among HIV-infected patients with PML at any stage of the disease, particularly in cases with extensive involvement.

Microlens array camera with variable apertures for single-shot high dynamic range (HDR) imaging.

We report a microlens array camera with variable apertures (MACVA) for high dynamic range (HDR) imaging by using microlens arrays with various sizes of apertures. The MACVA comprises variable apertures, microlens arrays, gap spacers, and a CMOS image sensor. The microlenses with variable apertures capture low dynamic range (LDR) images with different f-stops under single-shot exposure. The reconstructed HDR images clearly exhibit expanded dynamic ranges surpassing LDR images as well as high resolution without motion artifacts, comparable to the maximum MTF50 value observed among the LDR images. This compact camera provides, what we believe to be, a new perspective for various machine vision or mobile devices applications.

Analysis of the effectiveness of non-pharmaceutical interventions on influenza during the Coronavirus disease 2019 pandemic by time-series forecasting.

BACKGROUND: Coronavirus disease 2019 (COVID-19) was first identified in South Korea during the 2019-2020 seasonal influenza epidemic. The social distancing measures, as effective non-pharmaceutical interventions (NPIs), adopted to mitigate the spread of COVID-19 might have influenced influenza activity. We evaluated IFV(influenza virus) activity during the COVID-19 pandemic and the effect of NPI intensity on influenza transmission. METHODS: IFV activity and epidemic duration during COVID-19 pandemic were predicted under a counterfactual scenario with no NPIs against COVID-19. The Seasonal Autoregressive Integrated Moving Average Model was used to quantify the effects of NPIs on the transmission of influenza virus. Influenza-like illness/1000 outpatients and IFV positivity rate from the 2011-2012 to 2021-2022 seasons were used in this study. RESULTS: Comparison of the 2020-2021 and 2021-2022 seasonal influenza activities with those in 2013-2019 showed that COVID-19 outbreaks and associated NPIs such as face mask use, school closures, and travel restrictions reduced the influenza incidence by 91%. Without NPIs against COVID-19, the rates of influenza-like illness and IFV positivity would have been high during the influenza epidemic season, as in previous seasons. NPI intensity decreased the transmission of influenza; the magnitude of the reduction increased as the intensity of social-distancing measures increased (weak social distancing; step-by-step daily recovery: 58.10%, strong social distancing; special quarantine measures: 95.12%). CONCLUSIONS: Our results suggest that NPIs and personal hygiene can be used to suppress influenza transmission. NPIs against COVID-19 may be useful strategies for the prevention and control of influenza epidemics.

Vision for tobacco endgame in Korea: suggestions for countries with endgame aspirations.

Tobacco endgame is a focal point of discussion at both national and international levels. We aimed to describe efforts related to achieving the tobacco endgame in the Republic of Korea, an exemplar of a country with endgame aspirations, and compare them with the efforts of other nations. We reviewed the tobacco endgame efforts of three nations considered tobacco control leaders: New Zealand (NZ), Australia and Finland. The efforts/attempts of each country were described using an endgame strategy category. The tobacco control leaders had explicit goals to achieve a smoking prevalence of <5% before a target date and had legislation and research centres for tobacco control and/or endgame. NZ is implementing a mixture of conventional and innovative endgame interventions; the others use incremental conventional approaches. In Korea, there has been an attempt to ban the sale and manufacture of combustible cigarettes. The attempt led to the filing of a petition, and a survey of adults showed 70% supported the legislation banning tobacco. The Korean government mentioned a tobacco endgame in a 2019 plan, yet a target and an end date were absent. The 2019 plan in Korea included incremental FCTC strategies. Practices in the leading countries show that legislation and research are key to ending the tobacco epidemic. The MPOWER measures must be strengthened, endgame objectives must be set and bold strategies must be adopted. Key endgame policies include those with evidence of effectiveness, such as retailer reductions.

Contact system activation in disseminated intravascular coagulation: activities of prekallikrein and high-molecular-weight kininogen are significant risk factors.

The contact system activation can play a role in microthrombus formation of disseminated intravascular coagulation (DIC). This study investigated whether the activity of prekallikrein and high-molecular-weight kininogen (HMWK) correlated DIC progression. Contact system factors (prekallikrein, HMWK, activated factor XII), coagulation factors (IX, XI, XII) and tissue factor were measured in 140 patients who clinically suspected of having DIC. Prekallikrein and HMWK activity levels showed significant linear relationships with DIC score and antithrombin level, whereas prekallikrein and HMWK antigen levels did not. The activated factor XII, factor XII, factor XI and tissue factor were significant risk factors of overt-DIC. This finding suggests that consumption of prekallikrein and HMWK contributes to microvascular thrombosis in DIC. Measurements of prekallikrein and HMWK activity could be used as potential diagnostic markers for overt-DIC.

Real-world evidence of lupus anticoagulant testing: simultaneous positivity of diluted Russell's viper venom time and silica clotting time increases thrombotic risk prediction.

Lupus anticoagulant (LA) is composed of heterogeneous autoantibodies, which have a close association with thrombotic events. Due to its heterogeneity, two methods for increasing sensitivity are recommended for LA. An investigation of the thrombotic risk and anticardiolipin (aCL) and anti-ß2-glycoprotein I (aB2GPI) antibody profiles was conducted based on the results of using two parallel methods (dilute Russell viper venom time (dRVVT), silica clotting time (SCT)) in a real world clinical laboratory. Of 5120 patients, 684 patients (13%) were LA positive, and 422 patients (8%) experienced thrombotic events including pregnancy complication. Development of thrombotic events was more likely to occur in patients who were positive for both dRVVT and SCT compared with those who were positive for dRVVT or SCT only. In addition, significantly higher positive rates of aCL and aB2GPI and the persistently positive rate of LA at intervals of 12 weeks or longer were observed in patients who were positive for both dRVVT and SCT compared with those who were positive for dRVVT or SCT only. Considering three laboratory tests (LA, aCL, and aB2GPI), high thrombotic risk was observed for patients with both dRVVT and SCT positive LA results. A report on LA results that divides LA positive into two types (LA-single positive and LA-both positive) may be beneficial to clinicians in detection of high-risk thrombotic patients.

Transient Platelet Dysfunction in Congenital Factor XIII Deficiency with Enhanced Thrombin Generation Potential.

BACKGROUND: Congenital factor XIII (FXIII) deficiency is an extremely rare bleeding disorder with defects in the F13A1 or F13B genes. Here, we report a case of congenital FXIII deficiency patient who presented with trauma-induced intramuscular hemorrhage accompanied with transient platelet dysfunction with increased endogenous thrombin potential (ETP). METHODS: FXIII antigen and activity, F13A1 gene sequencing, and thrombin generation assay were measured. RESULTS: The diagnosis of FXIII deficiency was confirmed by a double heterozygous mutation of the F13A1 gene and decreased levels of FXIII antigen and activity. Platelet dysfunction caused by an antiplatelet drug was revealed in both platelet aggregation test and PFA-100. After a bleeding event, the PFA-100 results returned to normal and the thrombin generation assay in patient's plasma showed a higher ETP than normal. CONCLUSIONS: This increase in ETP may protect against bleeding and may explain why some patients show only a mild bleeding tendency despite undetectable FXIII activity.

New-Onset Seizures in Patients With COVID-19: A Case Series From a Single Public Hospital in Korea.

Seizure is an uncommon complication of coronavirus disease 2019 (COVID-19). The frequency and characteristics of new-onset seizures in hospitalized patients with COVID-19 were investigated. Of a total of 1,487 patients with confirmed COVID-19, six (0.4%) developed new-onset seizures. All six had severe or critical COVID-19 requiring intensive care and mechanical ventilation or high-flow oxygen therapy. Among COVID-19 patients admitted to the intensive care unit (n = 169), the incidence of new-onset seizures was 3.6%. Underlying structural lesions (acute infarction and remote hemorrhage), hypoxia, sepsis, and metabolic derangements were associated with the development of seizures. Of the six patients, three patients died, and, at the time of discharge, one patient had a severe disability, while the remaining two were well recovered.

Citric, succinic, and vanillic acid-functionalized magnetic-cored dendrimer for methylene blue adsorption.

A new functional composite was synthesized in this study comprising magnetic-cored dendrimer (MCD) modified with citric acid (CA), succinic acid (SA), and vanillic acid (VA) terminal groups. The CA-MCD, SA-MCD, and VA-MCD exhibited average particle size of 8-18 nm and superparamagnetic behavior. Adsorption potential of the composite was assessed by monitoring methylene blue (MB) removal from contaminated water. The CA-MCD attained adsorption equilibrium in 30 min while SA-MCD and VA-MCD achieved equilibrium in 60 min. The Langmuir model better fitted the adsorption results than the Freundlich model, indicating a monolayer mode of MB adsorption on the composite. Maximum adsorption capacity of CA-MCD, SA-MCD, and VA-MCD was 216.30 mg/g, 184.29 mg/g, and 196.58 mg/g, respectively. The CA-MCD exhibited best adsorption performance by removing 99% MB at pH = 11. In reusability experiments, the CA-MCD, SA-MCD, and VA-MCD maintained over 90% MB adsorption for both 15 mg/L and 50 mg/L solutions in the third cycle. Overall, the organic acid-functionalized MCDs with high adsorption capacity and reusability potential showed utility for practical application for wastewater decontamination.

Ultrathin arrayed camera for high-contrast near-infrared imaging.

We report an ultrathin arrayed camera (UAC) for high-contrast near infrared (NIR) imaging by using microlens arrays with a multilayered light absorber. The UAC consists of a multilayered composite light absorber, inverted microlenses, gap-alumina spacers and a planar CMOS image sensor. The multilayered light absorber was fabricated through lift-off and repeated photolithography processes. The experimental results demonstrate that the image contrast is increased by 4.48 times and the MTF 50 is increased by 2.03 times by eliminating optical noise between microlenses through the light absorber. The NIR imaging of UAC successfully allows distinguishing the security strip of authentic bill and the blood vessel of finger. The ultrathin camera offers a new route for diverse applications in biometric, surveillance, and biomedical imaging.

Peroxidasin is essential for endothelial cell survival and growth signaling by sulfilimine crosslink-dependent matrix assembly.

Peroxidasin (PXDN) has been reported to crosslink the C-terminal non-collagenous domains of collagen IV (Col IV) by forming covalent sulfilimine bond. Here, we explored the physiological role of PXDN and its mechanism of action in endothelial cell survival and growth. Silencing of PXDN using siRNAs decreased cell proliferation without increase of the number of detached cells and decreased cell viability under serum-starved condition with increased fragmented nuclei and caspase 3/7 activity. Conditioned medium (CM) containing wild-type PXDN restored the proliferation of PXDN-depleted cells, but CM containing mutant PXDN with deletion of either N-terminal extracellular matrix (ECM) motifs or peroxidase domain failed to restore PXDN function. Accordingly, anti-PXDN antibody [raised against IgC2 (3-4) subdomain within ECM motifs] and peroxidase inhibitor phloroglucinol prevented the rescue of the PXDN-depleted cells by PXDN-containing CM. PXDN depletion resulted in loss of sulfilimine crosslinks, and decreased dense fibrillar network assembly of not only Col IV, but also fibronectin and laminin like in Col IV knockdown. Exogenous PXDN-containing CM restored ECM assembly as well as proliferation of PXDN-depleted cells. Accordingly, purified recombinant PXDN protein restored the proliferation and ECM assembly, and prevented cell death of the PXDN-depleted cells. PXDN depletion also showed reduced growth factors-induced phosphorylation of FAK and ERK1/2. In addition, siPXDN-transfected cell-derived matrix failed to provide full ECM-mediated activation of FAK and ERK1/2. These results indicate that both the ECM motifs and peroxidase activity are essential for the cellular function of PXDN and that PXDN is crucial for ECM assembly for survival and growth signaling.

Double positivity of anti-ß2-glycoprotein I domain I and anti-phosphatidylserine/prothrombin antibodies enhances both thrombosis and positivity of anti-ADAMTS13 antibody.

Although a few antiphospholipid syndrome (APS) occurs with acquired thrombotic thrombocytopenic purpura (TTP), the relationship between antiphospholipid antibodies (aPL) and anti-ADAMTS13 (anti-a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) antibody remains uncertain. We investigated the relationship between high-risk thrombotic aPL and anti-ADAMTS13 antibody. Two hundred and thirty-seven patients with positive lupus anticoagulant and/or anticardiolipin antibody were included. Anti-ß2GPI (anti-ß2-glycoprotein I), anti-ß2GPIdI (anti-ß2-glycoprotein I domain I), anti-PS/PT (anti-phosphatidylserine and prothrombin), ADAMTS13 activity, and anti-ADAMTS13 antibody were measured. Double positivity of anti-ß2GPI and anti-PS/PT increased thrombotic risk more than three-fold and showed increased positivity of anti-ADAMTS13 antibody in comparison with the double negative group. Double positivity of anti-ß2GPIdI and anti-PS/PT presented both effects even more. In the linear regression analysis, double positivity of anti-ß2GPI and anti-PS/PT independently affected the anti-ADAMTS13 antibody level (ß = 1.982, P = 0.042). Our results revealed that double positivity of anti-ß2GPI or anti-ß2GPIdI and anti-PS/PT increased not only thrombotic risk but also the positivity of anti-ADAMTS13 antibody, especially indicating anti-ß2GPIdI showed a higher synergistic effect with anti-PS/PT. We suggest a possible association of anti-ADAMTS13 antibody with a high thrombotic risk of APS. Double positivity of anti-ß2GPI (anti-ß2-glycoprotein I) and anti-PS/PT (anti-phosphatidylserine and prothrombin) antibodies enhanced not only thrombotic risk but also positivity of anti-ADAMTS13 (anti-a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) antibody. Furthermore, double positivity of anti-ß2GPIdI (anti-ß2-glycoprotein I domain I) combined with anti-PS/PT even more elevated both thrombosis and positivity of anti-ADAMTS13 antibody. Double positivity of ß2GPI and anti-PS/PT was found as an independently significant contributing factor to anti-ADAMTS13 antibody level. We suggest the association between anti-ADAMTS13 antibody and the pathophysiology of antiphospholipid syndrome, which should be further evaluated.

Human induced pluripotent stem cell line banking for the production of rare blood type erythrocytes.

BACKGROUND: The in vitro production of mature human red blood cells (RBCs) from induced pluripotent stem cells (iPSCs) has been the focus of research to meet the high demand for blood transfusions. However, limitations like high costs and technological requirements restrict the use of RBCs produced by iPSC differentiation to specific circumstances, such as for patients with rare blood types or alloimmunized patients. In this study, we developed a detailed protocol for the generation of iPSC lines derived from peripheral blood of donors with O D-positive blood and rare blood types (D-and Jr(a-)) and subsequent erythroid differentiation. METHODS: Mononuclear cells separated from the peripheral blood of O D-positive and rare blood type donors were cultured to produce and expand erythroid progenitors and reprogrammed into iPSCs. A 31-day serum-free, xeno-free erythroid differentiation protocol was used to generate reticulocytes. The stability of iPSC lines was confirmed with chromosomal analysis and RT-PCR. Morphology and cell counts were determined by microscopy observations and flow cytometry. RESULTS: Cells from all donors were successfully used to generate iPSC lines, which were differentiated into erythroid precursors without any apparent chromosomal mutations. This differentiation protocol resulted in moderate erythrocyte yield per iPSC. CONCLUSIONS: It has previously only been hypothesized that erythroid differentiation from iPSCs could be used to produce RBCs for transfusion to patients with rare blood types or who have been alloimmunized. Our results demonstrate the feasibility of producing autologous iPSC-differentiated RBCs for clinical transfusions in patients without alternative options.

A Subset of Paracrine Factors as Efficient Biomarkers for Predicting Vascular Regenerative Efficacy of Mesenchymal Stromal/Stem Cells.

Mesenchymal stromal/stem cells (MSCs) have been developed as a promising source for cell-based therapies of ischemic disease. However, there are some hurdles in their clinical application such as poor cell engraftment and inconsistent stem cell potency. In this study, we sought to find biomarkers for predicting potency of MSCs for proangiogenic therapy to improve their beneficial effects. Large variations were observed in proangiogenic factor secretion profiles of conditioned media derived from nine different donor-derived Wharton's jelly (WJ)-derived MSCs and 8 factors among 55 angiogenesis-related factors were secreted at considerable levels. Two distinct WJ-MSCs that had the lowest or the highest secretion of these eight factors showed corresponding proangiogenic activities in in vitro angiogenesis assays. When four additional different donor-derived WJ-MSCs were further examined, proangiogenic activities in migration and tube formation of endothelial cells and in in vivo Matrigel plug assay were highly consistent with secretion levels of four major factors (angiogenin, interleukin-8, monocyte chemoattractant protein-1, and vascular endothelial growth factor). Such correlation was also observed in vascular regenerative effect in a mouse hind limb ischemia model. Blocking of these four factors by neutralizing antibodies or knockdown of them by siRNA treatment resulted in significant inhibition of proangiogenic activities of not only WJ-MSCs, but also bone marrow-derived MSCs. These results suggest that these four factors may represent efficient biomarkers for predicting vascular regenerative efficacy of MSCs. Stem Cells 2019;37:77-88.