R-SPONDIN2+ mesenchymal cells form the bud tip progenitor niche during human lung development

Renee F C Hein; Joshua H Wu; Emily M Holloway; Tristan Frum; Ansley S Conchola; Yu-Hwai Tsai; Angeline Wu; Alexis S Fine; Alyssa J Miller; Emmanuelle Szenker-Ravi; Kelley S Yan; Calvin J Kuo; Ian Glass; Bruno Reversade; Jason R Spence

doi:10.1016/j.devcel.2022.05.010

R-SPONDIN2⁺ mesenchymal cells form the bud tip progenitor niche during human lung development

Dev Cell. 2022 Jul 11;57(13):1598-1614.e8. doi: 10.1016/j.devcel.2022.05.010. Epub 2022 Jun 8.

Authors

Affiliations

¹ Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
² Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
³ Program in Cell and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁴ Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Singapore 138648, Singapore.
⁵ Columbia Center for Human Development, Columbia Stem Cell Initiative, Departments of Medicine and Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁶ Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁷ Department of Pediatrics, Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
⁸ Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Singapore 138648, Singapore; Laboratory of Human Genetics & Therapeutics, Institute of Molecular and Cell Biology (IMCB), A∗STAR, Singapore; Medical Genetics Department, Koç University School of Medicine (KUSOM), Istanbul, Turkey.
⁹ Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Program in Cell and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI 48109, USA. Electronic address: spencejr@umich.edu.

Abstract

The human respiratory epithelium is derived from a progenitor cell in the distal buds of the developing lung. These "bud tip progenitors" are regulated by reciprocal signaling with surrounding mesenchyme; however, mesenchymal heterogeneity and function in the developing human lung are poorly understood. We interrogated single-cell RNA sequencing data from multiple human lung specimens and identified a mesenchymal cell population present during development that is highly enriched for expression of the WNT agonist RSPO2, and we found that the adjacent bud tip progenitors are enriched for the RSPO2 receptor LGR5. Functional experiments using organoid models, explant cultures, and FACS-isolated RSPO2⁺ mesenchyme show that RSPO2 is a critical niche cue that potentiates WNT signaling in bud tip progenitors to support their maintenance and multipotency.

Keywords: R-Spondin2; RSPO2; bud tip progenitor; human development; lung development; lung mesenchyme; lung organoid; mesenchymal cell; single-cell RNA-seq; stem cell niche.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Humans
Lung
Mesenchymal Stem Cells*
Organogenesis*
Organoids
Wnt Signaling Pathway

Abstract

Publication types

MeSH terms

Grants and funding