A bioengineered niche promotes in vivo engraftment and maturation of pluripotent stem cell derived human lung organoids
- University of Michigan Medical School, United States
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
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).
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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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
Further reading
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- Stem Cells and Regenerative Medicine
Transplanting bioengineered human lung organoids into mice could lead to a humanized model for pre-clinical studies of lung disease.
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- Developmental Biology
- Stem Cells and Regenerative Medicine
Niches are often found in specific positions in tissues relative to the stem cells they support. Consistency of niche position suggests that placement is important for niche function. However, the complexity of most niches has precluded a thorough understanding of how their proper placement is established. To address this, we investigated the formation of a genetically tractable niche, the Drosophila Posterior Signaling Center (PSC), the assembly of which had not been previously explored. This niche controls hematopoietic progenitors of the lymph gland (LG). PSC cells were previously shown to be specified laterally in the embryo, but ultimately reside dorsally, at the LG posterior. Here, using live-imaging, we show that PSC cells migrate as a tight collective and associate with multiple tissues during their trajectory to the LG posterior. We find that Slit emanating from two extrinsic sources, visceral mesoderm and cardioblasts, is required for the PSC to remain a collective, and for its attachment to cardioblasts during migration. Without proper Slit-Robo signaling, PSC cells disperse, form aberrant contacts, and ultimately fail to reach their stereotypical position near progenitors. Our work characterizes a novel example of niche formation and identifies an extrinsic signaling relay that controls precise niche positioning.
