Document Type

Article

Publication Date

3-8-2022

Publication Title

Stem Cell Reports

Keywords

JMG

JAX Source

Stem Cell Reports 2022 Mar 8; 17(3):633-648

Volume

17

Issue

3

First Page

633

Last Page

648

ISSN

2213-6711

PMID

35120621

DOI

https://doi.org/10.1016/j.stemcr.2022.01.006

Grant

GM0103423

Abstract

Regeneration of amputated digit tips relies on mesenchymal progenitor cells and their differentiation into replacement bone and tissue stroma. Natural killer (NK) cells have well-characterized roles in antigen-independent killing of virally infected, pre-tumorous, or stressed cells; however, the potential for cytotoxic activity against regenerative progenitor cells is unclear. We identified NK cell recruitment to the regenerating digit tip, and NK cytotoxicity was observed against osteoclast and osteoblast progenitors. Adoptive cell transplants of spleen NK (SpNK) or thymus NK (ThNK) donor cells into immunodeficient mice demonstrated ThNK cell-induced apoptosis with a reduction in osteoclasts, osteoblasts, and proliferative cells, resulting in inhibition of regeneration. Adoptive transfer of NK cells deficient in NK cell activation genes identified that promotion of regeneration by SpNK cells requires Ncr1, whereas inhibition by ThNK cells is mediated via Klrk1 and perforin. Successful future therapies aimed at enhancing regeneration will require a deeper understanding of progenitor cell protection from NK cell cytotoxicity.

Comments

We acknowledge the JAX Center for Biometric Analysis for instrumentation, training, and technical support with mCT imaging (Doug Morris and Christine Wooley), the JAX imaging core and MDIBL Light Microscopy Facility (Fre´de´ric Bonnet), and the JAX Flow Cytometry Core for support (Will Schott); we also acknowledge JAX Histology Services (Elaine Bechtel) for technical support. We wish to thank Michael Sieweke, Eric Vivier, StephenWaggoner, and Derry Roopenian for critical mouse cell lines and animals and Nadia Rosenthal for critical infrastructure support.We thank Lilian Hyde for flow cytometry assistance and Khaled Dastagir for advice regarding cytotoxicity assays and mCT volumetric analysis. We thank Dustin Updike and Andrew Walter for careful reading of the manuscript.

This is an open access article under the CC BY-NC-ND license.

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