Non-invasive monitoring of chronic liver disease via near-infrared and shortwave-infrared imaging of endogenous lipofuscin

ABSTRACT Monitoring the progression of non-alcoholic fatty liver disease is hindered by a lack of suitable non-invasive imaging methods. Here, we show that the endogenous pigment lipofuscin

displays strong near-infrared and shortwave-infrared fluorescence when excited at 808 nm, enabling label-free imaging of liver injury in mice and the discrimination of pathological processes

from normal liver processes with high specificity and sensitivity. We also show that the near-infrared and shortwave-infrared fluorescence of lipofuscin can be used to monitor the

progression and regression of liver necroinflammation and fibrosis in mouse models of non-alcoholic fatty liver disease and advanced fibrosis, as well as to detect non-alcoholic

steatohepatitis and cirrhosis in biopsied samples of human liver tissue. Access through your institution Buy or subscribe This is a preview of subscription content, access via your

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institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS A NANOPARTICLE PROBE FOR THE IMAGING OF AUTOPHAGIC FLUX IN LIVE MICE VIA

MAGNETIC RESONANCE AND NEAR-INFRARED FLUORESCENCE Article 11 July 2022 LONG-TERM MONITORING OF INTRAVITAL BIOLOGICAL PROCESSES USING FLUORESCENT PROTEIN-ASSISTED NIR-II IMAGING Article Open

access 04 November 2022 NEAR-INFRARED II FLUORESCENCE IMAGING Article 04 April 2024 DATA AVAILABILITY The main data supporting the results in this study are available within the paper and

its Supplementary Information. The raw and analysed datasets generated during the study are too big to be publicly shared but are available for research purposes from the corresponding

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references ACKNOWLEDGEMENTS We thank S. Roberge for excellent technical support, W. Ho for RT-qPCR support and T. Reiberger for early discussions. This work received financial support, in

part, from the National Institutes of Health through the Laser Biomedical Research Center (grant no. 9-P41-EB015871-26A1 to M.G.B.) and the US Army Research Office through the Institute for

Soldier Nanotechnologies at MIT, under cooperative agreement no. W911NF-18-2-0048 (to M.G.B.). M.S. was supported by the National Science Foundation Graduate Research Fellowship Program

(grant no. 1122374). J.A.C. was supported by a National Defense Science and Engineering Graduate Fellowship 32 CFR 168a. K.v.L., Y.Z. and M.G.B. were supported by a Grand Challenges Grant

from the MGH/MIT Strategic Initiative. This work was also in part supported by grants from the National Foundation for Cancer Research, the Ludwig Center at Harvard, the US National Cancer

Institute (grant nos. P01-CA080124, R35-CA197743, R01-CA208205 and U01-CA224173 to R.K.J.). J.M.P. was supported by a NIH Training Grant (grant no. T32HL007627). This work was further

supported in part by the NIH (grant nos. R01 DK031036 and R01 DK033201 to C.R.K., and grant nos. K12 HD000850 and P30 DK40561) and a NASPGHAN Young Investigator/Nestle Nutrition Award to

S.S. M.P. was supported by an Erwin Schroedinger Fellowship from the Austrian Science Fund (FWF; project number J 3747-B28). S.C. was supported by an ABTA Basic Research Fellowship, MGH

Tosteon and Fund for Medical Discovery Fellowship and PCRF Emerging Investigator Fellowship Grant. O.T.B. was supported by a European Molecular Biology Organization long-term fellowship.

AUTHOR INFORMATION Author notes * Matthias Pinter Present address: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna,

Austria * Oliver T. Bruns Present address: Helmholtz Pioneer Campus, Helmholtz Zentrum München, Neuherberg, Germany * These authors contributed equally: Mari Saif, Wilhelmus J. Kwanten,

Jessica A. Carr, Ivy X. Chen. AUTHORS AND AFFILIATIONS * Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA Mari Saif, Jessica A. Carr, Juanye Zhang, Oliver

T. Bruns & Moungi G. Bawendi * Edwin L. Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

Wilhelmus J. Kwanten, Ivy X. Chen, Jessica M. Posada, Matthias Pinter, Sampurna Chatterjee & Rakesh K. Jain * Laboratory of Experimental Medicine and Pediatrics (LEMP)—Gastroenterology

and Hepatology, University of Antwerp, Wilrijk, Belgium Wilhelmus J. Kwanten * Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA Jessica M. Posada & Amitabh

Srivastava * Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA Yi Zheng & Klaus van Leyen * Joslin Diabetes Center,

Harvard Medical School, Boston, MA, USA Samir Softic & C. Ronald Kahn * Division of Gastroenterology, Boston Children’s Hospital, Boston, MA, USA Samir Softic * Division of

Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Kentucky College of Medicine and Kentucky Children’s Hospital, Lexington, KY, USA Samir Softic Authors *

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Ronald Kahn View author publications You can also search for this author inPubMed Google Scholar * Klaus van Leyen View author publications You can also search for this author inPubMed 

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author inPubMed Google Scholar * Moungi G. Bawendi View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS Conceptualization/evolution: W.J.K.,

J.A.C., I.X.C., M.P., K.v.L., O.T.B., R.K.J. and M.G.B. Formal analysis: M.S., W.J.K., J.A.C. and I.X.C. Funding acquisition: S.S., C.R.K., K.v.L., R.K.J. and M.G.B.

Investigation/experiments: M.S., W.J.K., J.A.C., I.X.C., J.M.P., J.Z., Y.Z., M.P. and S.C. Methodology: M.S., W.J.K., J.A.C., I.X.C., J.M.P., A.S., R.K.J. and M.G.B. Project management:

M.S., W.J.K. and J.A.C. Resources: S.S., C.R.K., K.v.L., R.K.J. and M.G.B. Supervision: R.K.J. and M.G.B. Validation: M.S., W.J.K. and J.A.C. Visualization: M.S. and J.A.C. Writing of the

original draft: M.S., W.J.K. and J.A.C. Writing, review and editing: all authors. CORRESPONDING AUTHORS Correspondence to Rakesh K. Jain or Moungi G. Bawendi. ETHICS DECLARATIONS COMPETING

INTERESTS M.P. is an investigator for Bayer, BMS and Lilly; a consultant for Bayer, BMS, Ipsen, Eisai and Lilly; and has received speaker honoraria from Bayer, BMS, Eisai and MSD as well as

travel support from Bayer and BMS. R.K.J. received honorarium from Amgen; consultant fees from Chugai, Merck, Ophthotech, Pfizer, SPARC, SynDevRx and XTuit; owns equity in Enlight,

Ophthotech, SynDevRx; and serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund and Tekla World Healthcare Fund.

M.G.B. is a consultant and owns equity in Lumicell Inc. Neither any reagent nor any funding from these organizations was used in this study. MIT and MGH have filed a patent (United States

application no. 62/654,665; international application no. PCT/US2019/026550) based on some of the findings described in this manuscript. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer

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figures and references. REPORTING SUMMARY SUPPLEMENTARY DATASET 1 Supplementary Tables 1–11. SUPPLEMENTARY DATASET 2 Statistical details. SUPPLEMENTARY VIDEO 1 Real-time and non-invasive

imaging of quantifiable autofluorescent pigments in rodent liver with progressive fibrosis. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Saif, M.,

Kwanten, W.J., Carr, J.A. _et al._ Non-invasive monitoring of chronic liver disease via near-infrared and shortwave-infrared imaging of endogenous lipofuscin. _Nat Biomed Eng_ 4, 801–813

(2020). https://doi.org/10.1038/s41551-020-0569-y Download citation * Received: 21 June 2019 * Accepted: 13 May 2020 * Published: 22 June 2020 * Issue Date: August 2020 * DOI:

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