1. Stem Cells and Regenerative Medicine
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A bioengineered niche promotes in vivo engraftment and maturation of pluripotent stem cell derived human lung organoids

  1. Briana R Dye
  2. Priya H Dedhia
  3. Alyssa J Miller
  4. Melinda S Nagy
  5. Eric S White
  6. Lonnie D Shea
  7. Jason R Spence  Is a corresponding author
  1. University of Michigan Medical School, United States
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Cite this article as: eLife 2016;5:e19732 doi: 10.7554/eLife.19732

Abstract

Human pluripotent stem cell (hPSC) derived tissues often remain developmentally immature in vitro, and become more adult-like in their structure, cellular diversity and function following transplantation into immunocompromised mice. Previously we have demonstrated that hPSC-derived human lung organoids (HLOs) resembled human fetal lung tissue in vitro (Dye et al. 2015). Here we show that HLOs required a bioartificial microporous Poly(lactide-co-glycolide) (PLG) scaffold niche for successful engraftment, long-term survival, and maturation of lung epithelium in vivo. Analysis of scaffold-grown transplanted tissue showed airway-like tissue with enhanced epithelial structure and organization compared to HLOs grown in vitro. By further comparing in vitro and in vivo grown HLOs with fetal and adult human lung tissue, we found that in vivo transplanted HLOs had improved cellular differentiation of secretory lineages that is reflective of differences between fetal and adult tissue, resulting in airway-like structures that were remarkably similar to the native adult human lung.

Article and author information

Author details

  1. Briana R Dye

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Priya H Dedhia

    Department of Surgery, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Alyssa J Miller

    Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Melinda S Nagy

    Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Eric S White

    Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Lonnie D Shea

    Center for Organogenesis, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jason R Spence

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    For correspondence
    spencejr@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7869-3992

Funding

National Heart, Lung, and Blood Institute (RO1 HL119215)

  • Jason R Spence

Unviersity of Michigan Cellular and Molecular Biology training grant (T32 GM007315)

  • Alyssa J Miller

University of Michigan Tissue Engineering and Regeneration Training Grant (DE00007057)

  • Alyssa J Miller

University of Michigan Rackham Graduate Fellowship

  • Briana R Dye

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All work using human pluripotent stem cells was approved by the University of Michigan Human Pluiripotent Stem Cell Research Oversight Committee (HPSCRO, application #1054). All human tissue used in this work was falls under NIH Exemption 4. The tissue was not obtained from living individuals, and was de-identified. Since this work falls under NIH Exemption 4, it was given a "not regulated" status by the University of Michigan IRB (protocol # HUM00093465 and HUM00105750). All animal experiments were approved by the University of Michigan Institutional Animal Care and Use Committee (IACUC; protocol # PRO00006609).

Reviewing Editor

  1. Janet Rossant, University of Toronto, Canada

Publication history

  1. Received: July 19, 2016
  2. Accepted: September 21, 2016
  3. Accepted Manuscript published: October 11, 2016 (version 1)
  4. Accepted Manuscript updated: September 29, 2016 (version 2)
  5. Version of Record published: November 1, 2016 (version 3)

Copyright

© 2016, Dye et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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Further reading

    1. Stem Cells and Regenerative Medicine
    Marko Z Nikolić, Emma L Rawlins
    Insight

    Transplanting bioengineered human lung organoids into mice could lead to a humanized model for pre-clinical studies of lung disease.

    1. Medicine
    2. Stem Cells and Regenerative Medicine
    Courtney Tindle et al.
    Tools and Resources Updated

    Background:

    SARS-CoV-2, the virus responsible for COVID-19, causes widespread damage in the lungs in the setting of an overzealous immune response whose origin remains unclear.

    Methods:

    We present a scalable, propagable, personalized, cost-effective adult stem cell-derived human lung organoid model that is complete with both proximal and distal airway epithelia. Monolayers derived from adult lung organoids (ALOs), primary airway cells, or hiPSC-derived alveolar type II (AT2) pneumocytes were infected with SARS-CoV-2 to create in vitro lung models of COVID-19.

    Results:

    Infected ALO monolayers best recapitulated the transcriptomic signatures in diverse cohorts of COVID-19 patient-derived respiratory samples. The airway (proximal) cells were critical for sustained viral infection, whereas distal alveolar differentiation (AT2→AT1) was critical for mounting the overzealous host immune response in fatal disease; ALO monolayers with well-mixed proximodistal airway components recapitulated both.

    Conclusions:

    Findings validate a human lung model of COVID-19, which can be immediately utilized to investigate COVID-19 pathogenesis and vet new therapies and vaccines.

    Funding:

    This work was supported by the National Institutes for Health (NIH) grants 1R01DK107585-01A1, 3R01DK107585-05S1 (to SD); R01-AI141630, CA100768 and CA160911 (to PG) and R01-AI 155696 (to PG, DS and SD); R00-CA151673 and R01-GM138385 (to DS), R01- HL32225 (to PT), UCOP-R00RG2642 (to SD and PG), UCOP-R01RG3780 (to P.G. and D.S) and a pilot award from the Sanford Stem Cell Clinical Center at UC San Diego Health (P.G, S.D, D.S). GDK was supported through The American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists. L.C.A's salary was supported in part by the VA San Diego Healthcare System. This manuscript includes data generated at the UC San Diego Institute of Genomic Medicine (IGC) using an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929).