1. Stem Cells and Regenerative Medicine

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
https://doi.org/10.7554/eLife.19732
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Cite this article
  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
(2016)
A bioengineered niche promotes in vivo engraftment and maturation of pluripotent stem cell derived human lung organoids
eLife 5:e19732.
https://doi.org/10.7554/eLife.19732
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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

Version 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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  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
(2016)
A bioengineered niche promotes in vivo engraftment and maturation of pluripotent stem cell derived human lung organoids
eLife 5:e19732.
https://doi.org/10.7554/eLife.19732

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Further reading

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    The attachment site of the rotator cuff (RC) is a classic fibrocartilaginous enthesis, which is the junction between bone and tendon with typical characteristics of a fibrocartilage transition zone. Enthesis development has historically been studied with lineage tracing of individual genes selected a priori, which does not allow for the determination of single-cell landscapes yielding mature cell types and tissues. Here, in together with open-source GSE182997 datasets (three samples) provided by Fang et al., we applied Single-cell RNA sequencing (scRNA-seq) to delineate the comprehensive postnatal RC enthesis growth and the temporal atlas from as early as postnatal day 1 up to postnatal week 8. And, we furtherly performed single-cell spatial transcriptomic sequencing on postnatal day 1 mouse enthesis, in order to deconvolute bone-tendon junction (BTJ) chondrocytes onto spatial spots. In summary, we deciphered the cellular heterogeneity and the molecular dynamics during fibrocartilage differentiation. Combined with current spatial transcriptomic data, our results provide a transcriptional resource that will support future investigations of enthesis development at the mechanistic level and may shed light on the strategies for enhanced RC healing outcomes.