Brandon Tyler Wesley, PhD

All Publications

• Four Decades of Progress in Heart-Lung Transplantation: 271 Cases at a Single Institution. The Journal of thoracic and cardiovascular surgery Elde, S., Baccouche, B. M., Mullis, D. M., Leipzig, M. M., Deuse, T., Krishnan, A., Fawad, M., Dale, R., Walsh, S., Padilla-Lopez, A., Wesley, B., He, H., Yajima, S., Zhu, Y., Wang, H., Guenthart, B. A., Shudo, Y., Reitz, B. A., Woo, Y. J. 2024

  Abstract

  OBJECTIVE: The objective of this study is to evaluate survival for combined heart-lung transplant (HLTx) recipients across four decades at a single institution. We aim to summarize our contemporary practice based upon more than 271 HLTx over 40 years.METHODS: Data were collected from a departmental database and the United Network for Organ Sharing (UNOS). Recipients <18y, those undergoing redo HLTx , or triple-organ system transplantation were excluded, leaving 271 patients for analysis. The Pioneering Era was defined by date of transplant between 1981-2000 (N=155), and the Modern Era between 2001-2022 (N=116). Survival analysis was performed using cardinality matching of populations based on donor and recipient age, donor and recipient sex, ischemic time, and sex-matching.RESULTS: Between 1981-2022, 271 HLTx were performed at a single institution. Recipients in the Modern Era were older (42 vs 34y, P<0.001) and had shorter waitlist times (78 vs 234d, P<0.001). Allografts from female donors were more common in the Modern Era (59% vs 39%, P=0.002). In the matched survival analysis, 30-day survival (97% vs 84%, P=0.005), 1-year survival (89% vs 77%, P=0.041), and 10-year survival (53% vs 26%, P=0.012) significantly improved in the Modern Era relative to the Pioneering Era, respectively.CONCLUSIONS: Long-term survival in HLTx is achievable with institutional experience and may continue to improve in the coming decades. Advances in mechanical circulatory support, improved maintenance immunosuppression, and early recognition and management of acute complications such as primary graft dysfunction and acute rejection have dramatically improved the prognosis for HLTx recipients in our contemporary institutional experience.

  View details for DOI 10.1016/j.jtcvs.2024.01.042

  View details for PubMedID 38320627

• Single-cell atlas of human liver development reveals pathways directing hepatic cell fates NATURE CELL BIOLOGY Wesley, B. T., Ross, A. B., Muraro, D., Miao, Z., Saxton, S., Tomaz, R. A., Morell, C. M., Ridley, K., Zacharis, E. D., Petrus-Reurer, S., Kraiczy, J., Mahbubani, K. T., Brown, S., Garcia-Bernardo, J., Alsinet, C., Gaffney, D., Horsfall, D., Tysoe, O. C., Botting, R. A., Stephenson, E., Popescu, D., MacParland, S., Bader, G., McGilvray, I. D., Ortmann, D., Sampaziotis, F., Saeb-Parsy, K., Haniffa, M., Stevens, K. R., Zilbauer, M., Teichmann, S. A., Vallier, L. 2022; 24 (10): 1487-+

  Abstract

  The liver has been studied extensively due to the broad number of diseases affecting its vital functions. However, therapeutic advances have been hampered by the lack of knowledge concerning human hepatic development. Here, we addressed this limitation by describing the developmental trajectories of different cell types that make up the human liver at single-cell resolution. These transcriptomic analyses revealed that sequential cell-to-cell interactions direct functional maturation of hepatocytes, with non-parenchymal cells playing essential roles during organogenesis. We utilized this information to derive bipotential hepatoblast organoids and then exploited this model system to validate the importance of signalling pathways in hepatocyte and cholangiocyte specification. Further insights into hepatic maturation also enabled the identification of stage-specific transcription factors to improve the functionality of hepatocyte-like cells generated from human pluripotent stem cells. Thus, our study establishes a platform to investigate the basic mechanisms directing human liver development and to produce cell types for clinical applications.

  View details for DOI 10.1038/s41556-022-00989-7

  View details for Web of Science ID 000854723100002

  View details for PubMedID 36109670

• Generation of functional hepatocytes by forward programming with nuclear receptors ELIFE Tomaz, R. A., Zacharis, E. D., Bachinger, F., Wurmser, A., Yamamoto, D., Petrus-Reurer, S., Morell, C. M., Dziedzicka, D., Wesley, B. T., Geti, I., Segeritz, C., de Brito, M. C., Chhatriwala, M., Ortmann, D., Saeb-Parsy, K., Vallier, L. 2022; 11

  Abstract

  Production of large quantities of hepatocytes remains a major challenge for a number of clinical applications in the biomedical field. Directed differentiation of human pluripotent stem cells (hPSCs) into hepatocyte-like cells (HLCs) provides an advantageous solution and a number of protocols have been developed for this purpose. However, these methods usually follow different steps of liver development in vitro, which is time consuming and requires complex culture conditions. In addition, HLCs lack the full repertoire of functionalities characterising primary hepatocytes. Here, we explore the interest of forward programming to generate hepatocytes from hPSCs and to bypass these limitations. This approach relies on the overexpression of three hepatocyte nuclear factors (HNF1A, HNF6, and FOXA3) in combination with different nuclear receptors expressed in the adult liver using the OPTi-OX platform. Forward programming allows for the rapid production of hepatocytes (FoP-Heps) with functional characteristics using a simplified process. We also uncovered that the overexpression of nuclear receptors such as RORc can enhance specific functionalities of FoP-Heps thereby validating its role in lipid/glucose metabolism. Together, our results show that forward programming could offer a versatile alternative to direct differentiation for generating hepatocytes in vitro.

  View details for DOI 10.7554/eLife.71591

  View details for Web of Science ID 000860501000001

  View details for PubMedID 35959725

  View details for PubMedCentralID PMC9374437

• TGF beta signalling is required to maintain pluripotency of human naive pluripotent stem cells ELIFE Osnato, A., Brown, S., Krueger, C., Andrews, S., Collier, A. J., Nakanoh, S., Londono, M., Wesley, B. T., Muraro, D., Brumm, A., Niakan, K. K., Vallier, L., Ortmann, D., Rugg-Gunn, P. J. 2021; 10

  Abstract

  The signalling pathways that maintain primed human pluripotent stem cells (hPSCs) have been well characterised, revealing a critical role for TGFβ/Activin/Nodal signalling. In contrast, the signalling requirements of naive human pluripotency have not been fully established. Here, we demonstrate that TGFβ signalling is required to maintain naive hPSCs. The downstream effector proteins - SMAD2/3 - bind common sites in naive and primed hPSCs, including shared pluripotency genes. In naive hPSCs, SMAD2/3 additionally bind to active regulatory regions near to naive pluripotency genes. Inhibiting TGFβ signalling in naive hPSCs causes the downregulation of SMAD2/3-target genes and pluripotency exit. Single-cell analyses reveal that naive and primed hPSCs follow different transcriptional trajectories after inhibition of TGFβ signalling. Primed hPSCs differentiate into neuroectoderm cells, whereas naive hPSCs transition into trophectoderm. These results establish that there is a continuum for TGFβ pathway function in human pluripotency spanning a developmental window from naive to primed states.

  View details for DOI 10.7554/eLife.67259

  View details for Web of Science ID 000692023000001

  View details for PubMedID 34463252

  View details for PubMedCentralID PMC8410071

• Cholangiocyte organoids regenerate human bile ducts Sampaziotis, F., Muraro, D., Tysoe, O. C., Sawiak, S., Beach, T., Godfrey, E., Upponi, S., Wesley, B., Brevini, T., Mahbubani, K., Berntsen, N., Mulcahy, V., Crick, K., Fear, C., Robinson, S., Swift, L., Corbett, G., Gelson, W., Mells, G., Davies, S., Amin, I., Gibbs, P., Teichmann, S., Butler, A., See, T., Melum, E., Watson, C., Saeb-Parsy, K., Vallier, L. ELSEVIER. 2021: S233-S234

  View details for Web of Science ID 000667753800063

• Cholangiocyte organoids can repair bile ducts after transplantation in the human liver SCIENCE Sampaziotis, F., Muraro, D., Tysoe, O. C., Sawiak, S., Beach, T. E., Godfrey, E. M., Upponi, S. S., Brevini, T., Wesley, B. T., Garcia-Bernardo, J., Mahbubani, K., Canu, G., Gieseck, R., Berntsen, N. L., Mulcahy, V. L., Crick, K., Fear, C., Robinson, S., Swift, L., Gambardella, L., Bargehr, J., Ortmann, D., Brown, S. E., Osnato, A., Murphy, M. P., Corbett, G., Gelson, W. H., Mells, G. F., Humphreys, P., Davies, S. E., Amin, I., Gibbs, P., Sinha, S., Teichmann, S. A., Butler, A. J., See, T., Melum, E., Watson, C. E., Saeb-Parsy, K., Vallier, L. 2021; 371 (6531): 839-+

  Abstract

  Organoid technology holds great promise for regenerative medicine but has not yet been applied to humans. We address this challenge using cholangiocyte organoids in the context of cholangiopathies, which represent a key reason for liver transplantation. Using single-cell RNA sequencing, we show that primary human cholangiocytes display transcriptional diversity that is lost in organoid culture. However, cholangiocyte organoids remain plastic and resume their in vivo signatures when transplanted back in the biliary tree. We then utilize a model of cell engraftment in human livers undergoing ex vivo normothermic perfusion to demonstrate that this property allows extrahepatic organoids to repair human intrahepatic ducts after transplantation. Our results provide proof of principle that cholangiocyte organoids can be used to repair human biliary epithelium.

  View details for DOI 10.1126/science.aaz6964

  View details for Web of Science ID 000619664700055

  View details for PubMedID 33602855

  View details for PubMedCentralID PMC7610478

• Regional Differences in Human Biliary Tissues and Corresponding In Vitro-Derived Organoids HEPATOLOGY Rimland, C. A., Tilson, S. G., Morell, C. M., Tomaz, R. A., Lu, W., Adams, S. E., Georgakopoulos, N., Otaizo-Carrasquero, F., Myers, T. G., Ferdinand, J. R., Gieseck, R. L., Sampaziotis, F., Tysoe, O. C., Ross, A., Kraiczy, J. M., Wesley, B., Muraro, D., Zilbauer, M., Oniscu, G. C., Hannan, N. F., Forbes, S. J., Saeb-Parsy, K., Wynn, T. A., Vallier, L. 2021; 73 (1): 247-267

  Abstract

  Organoids provide a powerful system to study epithelia in vitro. Recently, this approach was applied successfully to the biliary tree, a series of ductular tissues responsible for the drainage of bile and pancreatic secretions. More precisely, organoids have been derived from ductal tissue located outside (extrahepatic bile ducts; EHBDs) or inside the liver (intrahepatic bile ducts; IHBDs). These organoids share many characteristics, including expression of cholangiocyte markers such as keratin (KRT) 19. However, the relationship between these organoids and their tissues of origin, and to each other, is largely unknown.Organoids were derived from human gallbladder, common bile duct, pancreatic duct, and IHBDs using culture conditions promoting WNT signaling. The resulting IHBD and EHBD organoids expressed stem/progenitor markers leucine-rich repeat-containing G-protein-coupled receptor 5/prominin 1 and ductal markers KRT19/KRT7. However, RNA sequencing revealed that organoids conserve only a limited number of regional-specific markers corresponding to their location of origin. Of particular interest, down-regulation of biliary markers and up-regulation of cell-cycle genes were observed in organoids. IHBD and EHBD organoids diverged in their response to WNT signaling, and only IHBDs were able to express a low level of hepatocyte markers under differentiation conditions.Taken together, our results demonstrate that differences exist not only between extrahepatic biliary organoids and their tissue of origin, but also between IHBD and EHBD organoids. This information may help to understand the tissue specificity of cholangiopathies and also to identify targets for therapeutic development.

  View details for DOI 10.1002/hep.31252

  View details for Web of Science ID 000615369800019

  View details for PubMedID 32222998

  View details for PubMedCentralID PMC8641381

• Naive Pluripotent Stem Cells Exhibit Phenotypic Variability that Is Driven by Genetic Variation CELL STEM CELL Ortmann, D., Brown, S., Czechanski, A., Aydin, S., Muraro, D., Huang, Y., Tomaz, R. A., Osnato, A., Canu, G., Wesley, B. T., Skelly, D. A., Stegle, O., Choi, T., Churchill, G. A., Baker, C. L., Rugg-Gunn, P. J., Munger, S. C., Reinholdt, L. G., Vallier, L. 2020; 27 (3): 470-+

  Abstract

  Variability among pluripotent stem cell (PSC) lines is a prevailing issue that hampers not only experimental reproducibility but also large-scale applications and personalized cell-based therapy. This variability could result from epigenetic and genetic factors that influence stem cell behavior. Naive culture conditions minimize epigenetic fluctuation, potentially overcoming differences in PSC line differentiation potential. Here we derived PSCs from distinct mouse strains under naive conditions and show that lines from distinct genetic backgrounds have divergent differentiation capacity, confirming a major role for genetics in PSC phenotypic variability. This is explained in part through inconsistent activity of extra-cellular signaling, including the Wnt pathway, which is modulated by specific genetic variants. Overall, this study shows that genetic background plays a dominant role in driving phenotypic variability of PSCs.

  View details for DOI 10.1016/j.stem.2020.07.019

  View details for Web of Science ID 000565918500015

  View details for PubMedID 32795399

  View details for PubMedCentralID PMC7487768

• Cholangiocyte organoids are plastic and their identity is controlled by their local microenvironment Sampaziotis, F., Muraro, D., Tysoe, O. C., Beach, T., Sawiak, S., Godfrey, E., Upponi, S., Wesley, B., Garcia-Bernardo, J., Brevini, T., Mahbubani, K., Cannu, G., Gieseck, R., Berntsen, N., Mulcahy, V., Crick, K., Fear, C., Robinson, S., Swift, L., Ortmann, D., Osnato, A., Brown, S., Murphy, M., Gelson, W., Mells, G., Davies, S., Amin, I., Gibbs, P., Teichmann, S., Butler, A., See, T., Melum, E., Watson, C., Saeb-Parsy, K., Vallier, L. ELSEVIER. 2020: S112

  View details for Web of Science ID 000786587000182