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Fetal lung development via quantitative biomarkers from diffusion MRI and histological validation in rhesus macaques

Journal of Perinatology volume 42, pages 866–872 (2022)Cite this article

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Abstract

Objective

To demonstrate sensitivity of diffusion-weighted MRI (DW-MRI) to pulmonary cellular-space changes during normal in utero development using fetal rhesus macaques, compared to histological biomarkers.

Study design

In vivo/ex vivo DW-MRI was acquired in 26 fetal rhesus lungs (early-canalicular through saccular stages). Apparent diffusion coefficients (ADC) from MRI and tissue area density (H&E), alveolar type-II cells (ABCA3), and epithelial cells (TTF1) from histology were compared between gestational stages.

Results

In vivo/ex vivo ADC correlated with each other (Spearman ρ = 0.47, P = 0.038; Bland–Altman bias = 0.0835) and with area-density (in vivo ρ = -0.56, P = 0.011; ex vivo ρ = −0.83, P < 0.0001). In vivo/ex vivo ADC increased exponentially toward saturation with gestational stage (R2 = 0.49/0.49), while area-density decreased exponentially (R2 = 0.53). ABCA3 and TTF1 stains demonstrated expected fetal cellular development.

Conclusions

Fetal DW-MRI provides a non-invasive biomarker for pulmonary structural maturation, with a strong correlation to histological markers during tissue development in rhesus macaques. This method has strong potential for assessing human fetal development, particularly in patients with pulmonary hypoplasia.

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Fig. 1: Representative fetal lung data at the early-canalicular (top row), mid-canalicular (middle row), and saccular stages (bottom row).
Fig. 2: Changes in fetal pulmonary development via diffusion MRI and quantitative histology.
Fig. 3: Comparison of fetal lung ADC from in vivo and ex vivo diffusion MRI.
Fig. 4: Comparison of in vivo and ex vivo fetal lung ADC with quantitative histology.

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Acknowledgements

The authors thank the Oregon National Primate Research Center and the Imaging Research Center at Cincinnati Children’s Hospital. This publication was made possible, in part, using the Cincinnati Children’s Confocal Imaging Center; we specifically acknowledge Evan Meyer for assistance with tissue area-density measurements.

Author contributions

NSH/XC/JG/XW/ALF prepared samples and performed experiments. CDK/JPB/JCW supervised work. NSH/XC wrote manuscript. All authors provided feedback and shaped analysis, interpretation, and manuscript.

Funding

National Institutes of Health: R01 AA021981, R01 HL131634, and T32 HL007752. The Research Foundation at Cincinnati Children’s Hospital.

Author information

Author notes

  1. James P. Bridges

    Present address: Department of Medicine, National Jewish Health, Denver, CO, USA

Authors and Affiliations

  1. Center for Pulmonary Imaging Research, Division of Pulmonary Medicine and Department of Radiology, Cincinnati Children’s Hospital, Cincinnati, OH, USA

    Nara S. Higano, Xuefeng Cao, Jinbang Guo & Jason C. Woods

  2. Bronchopulmonary Dysplasia Center, Cincinnati Children’s Hospital, Cincinnati, OH, USA

    Nara S. Higano & Jason C. Woods

  3. Division of Pulmonary Medicine, Cincinnati Children’s Hospital, Cincinnati, OH, USA

    Nara S. Higano, Jinbang Guo & Jason C. Woods

  4. Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA

    Nara S. Higano & Jason C. Woods

  5. Department of Radiology, Cincinnati Children’s Hospital, Cincinnati, OH, USA

    Nara S. Higano & Jason C. Woods

  6. Department of Physics, University of Cincinnati, Cincinnati, OH, USA

    Xuefeng Cao & Jason C. Woods

  7. Division of Neuroscience, Oregon National Primate Research Center and Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR, USA

    Xiaojie Wang & Christopher D. Kroenke

  8. Division of Neonatology and Pulmonary Biology, Cincinnati Children’s Hospital, Cincinnati, OH, USA

    Alyssa L. Filuta & James P. Bridges

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Correspondence to Nara S. Higano.

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Higano, N.S., Cao, X., Guo, J. et al. Fetal lung development via quantitative biomarkers from diffusion MRI and histological validation in rhesus macaques. J Perinatol 42, 866–872 (2022). https://doi.org/10.1038/s41372-021-01236-x

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