gms | German Medical Science

62. Kongress der Deutschen Gesellschaft für Handchirurgie

Deutsche Gesellschaft für Handchirurgie

06. bis 08. Oktober 2022, Garmisch-Partenkirchen

Immunoregulatory role of organ-specific NK cells in P3 digit tip regeneration

Meeting Abstract

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  • corresponding author presenting/speaker Nadjib Dastagir - Medizinische Hochschule Hannover, Jackson Laboratory, Mount Desert Island Biological Laboratory, Hannover, Germany
  • James Godwin - Jackson Laboratory, Mount Desert Island Biological Laboratory, Bar Harbor, Germany

Deutsche Gesellschaft für Handchirurgie. 62. Kongress der Deutschen Gesellschaft für Handchirurgie. Garmisch-Partenkirchen, 06.-08.10.2022. Düsseldorf: German Medical Science GMS Publishing House; 2022. Doc22dgh12

doi: 10.3205/22dgh12, urn:nbn:de:0183-22dgh120

Published: October 6, 2022

© 2022 Dastagir et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.


Outline

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Objectives: Mammalian digit injuries often regenerate poorly, in contrast to other non-vertebrate regenerative models. This diminished regenerative ability requires the need for amputations and subsequent reconstructions, which are not only traumatic events for the patients, but also have an enormous impact on their quality of life. Several factors contribute to this including the immune response and genetic predispositions resulting in a propensity for vasoconstriction and vascular inflammation. Recently, it was observed that on the genetic level, the developmental Wnt and sonic hedgehog signaling pathways play an important role in regenerative ability. These findings suggest a crosstalk between the epidermal-mesenchyme germ layers. To further study the role of this crosstalk and thus improve the regenerative process in mammals, we must understand the post-injury inflammatory response and subsequent cell interactions that contribute to wound healing. Thus, the mouse digit-tip regeneration model has analogous potential to regenerate similar injuries in human patients. Unlocking latent regeneration potential in mammals or developing future therapies will rely on understanding the factors that regulate successful regeneration in model systems.

Method: Using FACS, trichrome histology, immunofluorescence and microCT imaging, distinct differences were observed with NK cell treatments of different origins. Splenic NK cell-treated NSG mice show accelerated regeneration, having the most complete overall morphology and largest bone volume of all treatment groups.

Results and Conclusion: Adoptive cell transfer experiments reveal that spleen-derived NK cells promote histolysis and blastema formation through increasing proliferation of osteoclasts, whereas NK cells from the thymus delay regeneration of both soft and hard-tissue via apoptosis of mesenchymal stem cells. Furthermore, NK cells control monocyte differentiation to effector phenotypes, such as osteoclasts. Leveraging a series of mouse models deficient for genes important to natural killer cell function, we show that the limb regeneration-promoting action of splenic NK cells requires Ncr1, while the negative action of thymic NK cells is mediated via Klrk1 and perforin. Our findings yield insight into mammalian digit tip regeneration and demonstrate the importance of NK cells on regenerative ability. Additionally, these results may be translated to clinical research and improve the treatment strategies for enhancing regeneration in humans.