Xiaokang Wu

All Publications

• Abstract 11641: The Role of Inflammation in a Humanized Mouse Model of Transthyretin Cardiac Amyloidosis American Heart Association-Scientific Session Wu, X. 2023
• Cell therapy attenuates endothelial dysfunction in hypertensive rats with heart failure and preserved ejection fraction. American journal of physiology. Heart and circulatory physiology de Couto, G., Mesquita, T., Wu, X., Rajewski, A., Huang, F., Akhmerov, A., Na, N., Wu, D., Wang, Y., Li, L., Tran, M., Kilfoil, P., Cingolani, E., Marbán, E. 2022; 323 (5): H892-H903

  Abstract

  Heart failure with preserved ejection fraction (HFpEF) is defined by increased left ventricular (LV) stiffness, impaired vascular compliance, and fibrosis. Although systemic inflammation, driven by comorbidities, has been proposed to play a key role, the precise pathogenesis remains elusive. To test the hypothesis that inflammation drives endothelial dysfunction in HFpEF, we used cardiosphere-derived cells (CDCs), which reduce inflammation and fibrosis, improving function, structure, and survival in HFpEF rats. Dahl salt-sensitive rats fed a high-salt diet developed HFpEF, as manifested by diastolic dysfunction, systemic inflammation, and accelerated mortality. Rats were randomly allocated to receive intracoronary infusion of CDCs or vehicle. Two weeks later, inflammation, oxidative stress, and endothelial function were analyzed. Single-cell RNA sequencing of heart tissue was used to assay transcriptomic changes. CDCs improved endothelial-dependent vasodilation while reducing oxidative stress and restoring endothelial nitric oxide synthase (eNOS) expression. RNA sequencing revealed CDC-induced attenuation of pathways underlying endothelial cell leukocyte binding and innate immunity. Exposure of endothelial cells to CDC-secreted extracellular vesicles in vitro reduced VCAM-1 protein expression and attenuated monocyte adhesion and transmigration. Cell therapy with CDCs corrects diastolic dysfunction, reduces oxidative stress, and restores vascular reactivity. These findings lend credence to the hypothesis that inflammatory changes of the vascular endothelium are important, if not central, to HFpEF pathogenesis.NEW & NOTEWORTHY We tested the concept that inflammation of endothelial cells is a major pathogenic factor in HFpEF. CDCs are heart-derived cell products with verified anti-inflammatory therapeutic properties. Infusion of CDCs reduced oxidative stress, restored eNOS abundance, lowered monocyte levels, and rescued the expression of multiple disease-associated genes, thereby restoring vascular reactivity. The salutary effects of CDCs support the hypothesis that inflammation of endothelial cells is a proximate driver of HFpEF.

  View details for DOI 10.1152/ajpheart.00287.2022

  View details for PubMedID 36083797

  View details for PubMedCentralID PMC9602891

• Inhibitory effect of lanosterol on cataractous lens of cynomolgus monkeys using a subconjunctival drug release system. Precision clinical medicine Zhang, K., He, W., Du, Y., Zhou, Y., Wu, X., Zhu, J., Zhu, X., Zhang, K., Lu, Y. 2022; 5 (3): pbac021

  Abstract

  To evaluate the effect of lanosterol on cataractous lens of cynomolgus monkeys using a subconjunctival drug release system.Nine elder cynomolgus monkeys were used, consisting of three monkeys without cataract as controls, three monkeys with naturally occurring cortical cataract, and three monkeys with nuclear cataract as intervention groups. Nanoparticulated thermogel with lanosterol and fluorescein was administered by subconjunctival injection in the monkeys with cataract. Fluorescence changes of injected thermogel and cataract progression were observed. Lanosterol concentration in aqueous humor, solubility changes in lens proteins, and oxidative stress levels were analyzed in the lenses of the control and intervention groups.Injected thermogel showed decreased fluorescence during follow up. Lanosterol concentration in aqueous humor increased in the first 2 weeks and then gradually decreased, which was in accordance with the changes in cortical lens clarity. However, lenses with nuclear opacification showed little change. In the cortical region of lenses with cortical cataract, solubility of α-crystallin was significantly increased after administration of lanosterol, as well as the reduction of oxidative stress.We demonstrated the effect of lanosterol on cataract progression based on in vivo models of primates. Lanosterol showed a short-term and reliable reversal effect on reducing cataract severity in cortical cataract in the early stages, possibly due to the increase in the solubility of lens proteins and changes in the oxidative stress status. Lanosterol administration using subconjunctival drug release system could be a promising nonsurgical approach for future clinical studies of cataract prevention and treatment.

  View details for DOI 10.1093/pcmedi/pbac021

  View details for PubMedID 36196296

  View details for PubMedCentralID PMC9523460

• Rapid 3D bioprinting of a multicellular model recapitulating pterygium microenvironment BIOMATERIALS Zhong, Z., Wang, J., Tian, J., Deng, X., Balayan, A., Sun, Y., Xiang, Y., Guan, J., Schimelman, J., Hwang, H., You, S., Wu, X., Ma, C., Shi, X., Yao, E., Deng, S. X., Chen, S. 2022; 282: 121391

  Abstract

  Pterygium is an ocular surface disorder with high prevalence that can lead to vision impairment. As a pathological outgrowth of conjunctiva, pterygium involves neovascularization and chronic inflammation. Here, we developed a 3D multicellular in vitro pterygium model using a digital light processing (DLP)-based 3D bioprinting platform with human conjunctival stem cells (hCjSCs). A novel feeder-free culture system was adopted and efficiently expanded the primary hCjSCs with homogeneity, stemness and differentiation potency. The DLP-based 3D bioprinting method was able to fabricate hydrogel scaffolds that support the viability and biological integrity of the encapsulated hCjSCs. The bioprinted 3D pterygium model consisted of hCjSCs, immune cells, and vascular cells to recapitulate the disease microenvironment. Transcriptomic analysis using RNA sequencing (RNA-seq) identified a distinct profile correlated to inflammation response, angiogenesis, and epithelial mesenchymal transition in the bioprinted 3D pterygium model. In addition, the pterygium signatures and disease relevance of the bioprinted model were validated with the public RNA-seq data from patient-derived pterygium tissues. By integrating the stem cell technology with 3D bioprinting, this is the first reported 3D in vitro disease model for pterygium that can be utilized for future studies towards personalized medicine and drug screening.

  View details for DOI 10.1016/j.biomaterials.2022.121391

  View details for Web of Science ID 000788717500002

  View details for PubMedID 35101743

• Cardioprotection in ischemia-reperfusion injury achieved by a single amino acid substitution of NCX1 (H165A) The Biophysics Society Zhang, R., Wu, X., Xie, C., Gonzalez, D., Norris, R., Li, L., John, S. A., Philipson, K. D., Ottolia, M., Goldhaber, J. I. 2022

  View details for DOI 10.1016/j.bpj.2021.11.2272

• Bioprinting of dual ECM scaffolds encapsulating limbal stem/progenitor cells in active and quiescent statuses. Biofabrication Zhong, Z., Balayan, A., Tian, J., Xiang, Y., Hwang, H. H., Wu, X., Deng, X., Schimelman, J., Sun, Y., Ma, C., Dos Santos, A., You, S., Tang, M., Yao, E., Shi, X., Steinmetz, N. F., Deng, S. X., Chen, S. 2021; 13 (4)

  Abstract

  Limbal stem cell deficiency and corneal disorders are among the top global threats for human vision. Emerging therapies that integrate stem cell transplantation with engineered hydrogel scaffolds for biological and mechanical support are becoming a rising trend in the field. However, methods for high-throughput fabrication of hydrogel scaffolds, as well as knowledge of the interaction between limbal stem/progenitor cells (LSCs) and the surrounding extracellular matrix (ECM) are still much needed. Here, we employed digital light processing (DLP)-based bioprinting to fabricate hydrogel scaffolds encapsulating primary LSCs and studied the ECM-dependent LSC phenotypes. The DLP-based bioprinting with gelatin methacrylate (GelMA) or hyaluronic acid glycidyl methacrylate (HAGM) generated microscale hydrogel scaffolds that could support the viability of the encapsulated primary rabbit LSCs (rbLSCs) in culture. Immunocytochemistry and transcriptional analysis showed that the encapsulated rbLSCs remained active in GelMA-based scaffolds while exhibited quiescence in the HAGM-based scaffolds. The primary human LSCs encapsulated within bioprinted scaffolds showed consistent ECM-dependent active/quiescent statuses. Based on these results, we have developed a novel bioprinted dual ECM 'Yin-Yang' model encapsulating LSCs to support both active and quiescent statues. Our findings provide valuable insights towards stem cell therapies and regenerative medicine for corneal reconstruction.

  View details for DOI 10.1088/1758-5090/ac1992

  View details for PubMedID 34330126

  View details for PubMedCentralID PMC8716326

• Exosomally derived Y RNA fragment alleviates hypertrophic cardiomyopathy in transgenic mice. Molecular therapy. Nucleic acids Huang, F., Na, N., Ijichi, T., Wu, X., Miyamoto, K., Ciullo, A., Tran, M., Li, L., Ibrahim, A., Marbán, E., de Couto, G. 2021; 24: 951-960

  Abstract

  Cardiosphere-derived cell exosomes (CDCexo) and YF1, a CDCexo-derived non-coding RNA, elicit therapeutic bioactivity in models of myocardial infarction and hypertensive hypertrophy. Here we tested the hypothesis that YF1, a 56-nucleotide Y RNA fragment, could alleviate cardiomyocyte hypertrophy, inflammation, and fibrosis associated with hypertrophic cardiomyopathy (HCM) in transgenic mice harboring a clinically relevant mutation in cardiac troponin I (cTnIGly146). By quantitative PCR, YF1 was detectable in bone marrow, spleen, liver, and heart 30 min after intravenous (i.v.) infusion. For efficacy studies, mice were randomly allocated to receive i.v. YF1 or vehicle, monitored for ambulatory and cardiac function, and sacrificed at 4 weeks. YF1 (but not vehicle) improved ambulation and reduced cardiac hypertrophy and fibrosis. In parallel, peripheral mobilization of neutrophils and proinflammatory monocytes was decreased, and fewer macrophages infiltrated the heart. RNA-sequencing of macrophages revealed that YF1 confers substantive and broad changes in gene expression, modulating pathways associated with immunological disease and inflammatory responses. Together, these data demonstrate that YF1 can reverse hypertrophic and fibrotic signaling pathways associated with HCM, while improving function, raising the prospect that YF1 may be a viable novel therapeutic candidate for HCM.

  View details for DOI 10.1016/j.omtn.2021.04.014

  View details for PubMedID 34094713

  View details for PubMedCentralID PMC8141670

• Rapid bioprinting of conjunctival stem cell micro-constructs for subconjunctival ocular injection. Biomaterials Zhong, Z., Deng, X., Wang, P., Yu, C., Kiratitanaporn, W., Wu, X., Schimelman, J., Tang, M., Balayan, A., Yao, E., Tian, J., Chen, L., Zhang, K., Chen, S. 2021; 267: 120462

  Abstract

  Ocular surface diseases including conjunctival disorders are multifactorial progressive conditions that can severely affect vision and quality of life. In recent years, stem cell therapies based on conjunctival stem cells (CjSCs) have become a potential solution for treating ocular surface diseases. However, neither an efficient culture of CjSCs nor the development of a minimally invasive ocular surface CjSC transplantation therapy has been reported. Here, we developed a robust in vitro expansion method for primary rabbit-derived CjSCs and applied digital light processing (DLP)-based bioprinting to produce CjSC-loaded hydrogel micro-constructs for injectable delivery. Expansion medium containing small molecule cocktail generated fast dividing and highly homogenous CjSCs for more than 10 passages in feeder-free culture. Bioprinted hydrogel micro-constructs with tunable mechanical properties enabled the 3D culture of CjSCs while supporting viability, stem cell phenotype, and differentiation potency into conjunctival goblet cells. These hydrogel micro-constructs were well-suited for scalable dynamic suspension culture of CjSCs and were successfully delivered to the bulbar conjunctival epithelium via minimally invasive subconjunctival injection. This work integrates novel cell culture strategies with bioprinting to develop a clinically relevant injectable-delivery approach for CjSCs towards the stem cell therapies for the treatment of ocular surface diseases.

  View details for DOI 10.1016/j.biomaterials.2020.120462

  View details for PubMedID 33129190

  View details for PubMedCentralID PMC7719077

• Abstract 11475: A Genetically Modified pH Resistant NCX1 Mouse Prevents Calcium Overload During Acidosis and is Cardioprotective American Heart Association Zhang, R., Wu, X., et al 2021

  View details for DOI 10.1161/circ.144.suppl_1.11475

• Evaluation and accurate diagnoses of pediatric diseases using artificial intelligence NATURE MEDICINE Liang, H., Tsui, B. Y., Ni, H., Valentim, C. S., Baxter, S. L., Liu, G., Cai, W., Kermany, D. S., Sun, X., Chen, J., He, L., Zhu, J., Tian, P., Shao, H., Zheng, L., Hou, R., Hewett, S., Li, G., Liang, P., Zang, X., Zhang, Z., Pan, L., Cai, H., Ling, R., Li, S., Cui, Y., Tang, S., Ye, H., Huang, X., He, W., Liang, W., Zhang, Q., Jiang, J., Yu, W., Gao, J., Ou, W., Deng, Y., Hou, Q., Wang, B., Yao, C., Liang, Y., Zhang, S., Duan, Y., Zhang, R., Gibson, S., Zhang, C. L., Li, O., Zhang, E. D., Karin, G., Nguyen, N., Wu, X., Wen, C., Xu, J., Xu, W., Wang, B., Wang, W., Li, J., Pizzato, B., Bao, C., Xiang, D., He, W., He, S., Zhou, Y., Haw, W., Goldbaum, M., Tremoulet, A., Hsu, C., Carter, H., Zhu, L., Zhang, K., Xia, H. 2019; 25 (3): 433-+

  Abstract

  Artificial intelligence (AI)-based methods have emerged as powerful tools to transform medical care. Although machine learning classifiers (MLCs) have already demonstrated strong performance in image-based diagnoses, analysis of diverse and massive electronic health record (EHR) data remains challenging. Here, we show that MLCs can query EHRs in a manner similar to the hypothetico-deductive reasoning used by physicians and unearth associations that previous statistical methods have not found. Our model applies an automated natural language processing system using deep learning techniques to extract clinically relevant information from EHRs. In total, 101.6 million data points from 1,362,559 pediatric patient visits presenting to a major referral center were analyzed to train and validate the framework. Our model demonstrates high diagnostic accuracy across multiple organ systems and is comparable to experienced pediatricians in diagnosing common childhood diseases. Our study provides a proof of concept for implementing an AI-based system as a means to aid physicians in tackling large amounts of data, augmenting diagnostic evaluations, and to provide clinical decision support in cases of diagnostic uncertainty or complexity. Although this impact may be most evident in areas where healthcare providers are in relative shortage, the benefits of such an AI system are likely to be universal.

  View details for DOI 10.1038/s41591-018-0335-9

  View details for Web of Science ID 000460643100021

  View details for PubMedID 30742121

• Liu et al. reply. Nature Liu, Y., Granet, D., Lin, H., Baxter, S., Ouyang, H., Zhu, J., Huang, S., Liu, Z., Wu, X., Yan, F., Liu, X., Luo, L., Heichel, C., Zhang, M., Cai, W., Maas, R. L., Zhang, K. 2018; 556 (7699): E3-E4

  View details for DOI 10.1038/nature26150

  View details for PubMedID 29620731

• Identifying Medical Diagnoses and Treatable Diseases by Image-Based Deep Learning. Cell Kermany, D. S., Goldbaum, M. n., Cai, W. n., Valentim, C. C., Liang, H. n., Baxter, S. L., McKeown, A. n., Yang, G. n., Wu, X. n., Yan, F. n., Dong, J. n., Prasadha, M. K., Pei, J. n., Ting, M. n., Zhu, J. n., Li, C. n., Hewett, S. n., Dong, J. n., Ziyar, I. n., Shi, A. n., Zhang, R. n., Zheng, L. n., Hou, R. n., Shi, W. n., Fu, X. n., Duan, Y. n., Huu, V. A., Wen, C. n., Zhang, E. D., Zhang, C. L., Li, O. n., Wang, X. n., Singer, M. A., Sun, X. n., Xu, J. n., Tafreshi, A. n., Lewis, M. A., Xia, H. n., Zhang, K. n. 2018; 172 (5): 1122–31.e9

  Abstract

  The implementation of clinical-decision support algorithms for medical imaging faces challenges with reliability and interpretability. Here, we establish a diagnostic tool based on a deep-learning framework for the screening of patients with common treatable blinding retinal diseases. Our framework utilizes transfer learning, which trains a neural network with a fraction of the data of conventional approaches. Applying this approach to a dataset of optical coherence tomography images, we demonstrate performance comparable to that of human experts in classifying age-related macular degeneration and diabetic macular edema. We also provide a more transparent and interpretable diagnosis by highlighting the regions recognized by the neural network. We further demonstrate the general applicability of our AI system for diagnosis of pediatric pneumonia using chest X-ray images. This tool may ultimately aid in expediting the diagnosis and referral of these treatable conditions, thereby facilitating earlier treatment, resulting in improved clinical outcomes. VIDEO ABSTRACT.

  View details for PubMedID 29474911