Nail-associated mesenchymal cells contribute to and are essential for dorsal digit tip regeneration

Neemat Mahmud; Christine Eisner; Sruthi Purushothaman; Mekayla A Storer; David R Kaplan; Freda D Miller

doi:10.1016/j.celrep.2022.111853

Nail-associated mesenchymal cells contribute to and are essential for dorsal digit tip regeneration

Cell Rep. 2022 Dec 20;41(12):111853. doi: 10.1016/j.celrep.2022.111853.

Authors

Neemat Mahmud¹, Christine Eisner², Sruthi Purushothaman², Mekayla A Storer³, David R Kaplan⁴, Freda D Miller⁵

Affiliations

¹ Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5G 1A8, Canada.
² Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
³ Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
⁴ Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1A8, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z, Canada.
⁵ Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5G 1A8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1A8, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z, Canada. Electronic address: freda.miller@msl.ubc.ca.

PMID: 36543145
DOI: 10.1016/j.celrep.2022.111853

Abstract

Here, we ask why the nail base is essential for mammalian digit tip regeneration, focusing on the inductive nail mesenchyme. We identify a transcriptional signature for these cells that includes Lmx1b and show that the Lmx1b-expressing nail mesenchyme is essential for blastema formation. We use a combination of Lmx1bCreERT2-based lineage-tracing and single-cell transcriptional analyses to show that the nail mesenchyme contributes cells for two pro-regenerative mechanisms. One group of cells maintains their identity and regenerates the new nail mesenchyme. A second group contributes specifically to the dorsal blastema, loses their nail mesenchyme phenotype, acquires a blastema transcriptional state that is highly similar to blastema cells of other origins, and ultimately contributes to regeneration of the dorsal but not ventral dermis and bone. Thus, the regenerative necessity for an intact nail base is explained, at least in part, by a requirement for the inductive nail mesenchyme.

Keywords: CP: Developmental biology; CP: Stem cell research; Lmx1b; blastema; cell ablation; digit tip regeneration; mesenchymal cells; nail mesenchyme; regeneration; single cell transcriptomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone and Bones
Cells, Cultured
Extremities
Mammals
Mesenchymal Stem Cells*

Grants and funding

CIHR/Canada