The Jackson Laboratory, Bar Harbor, ME 04609, USA; Mount Desert Island Biological Laboratory, Kathryn W. Davis Center for Regenerative Biology and Aging, Salisbury Cove, ME 04609, USA; Medical School of Hanover, 30659 Hannover, Germany.
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Stem Cell Reports. 2022 Mar 8;17(3):633-648. doi: 10.1016/j.stemcr.2022.01.006. Epub 2022 Feb 3.
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.
断指指尖的再生依赖于间充质祖细胞及其分化为替代骨和组织基质。自然杀伤 (NK) 细胞在非抗原依赖性杀伤病毒感染、前瘤或应激细胞方面具有明确的作用；然而，针对再生祖细胞的细胞毒性活性尚不清楚。我们发现 NK 细胞募集到再生的指尖，并且观察到 NK 细胞对破骨细胞和成骨细胞祖细胞的细胞毒性作用。将脾 NK（SpNK）或胸腺 NK（ThNK）供体细胞的过继细胞移植到免疫缺陷小鼠中，表明 ThNK 细胞诱导凋亡，导致破骨细胞、成骨细胞和增殖细胞减少，从而抑制再生。NK 细胞激活基因缺陷型 NK 细胞的过继转移表明，SpNK 细胞促进再生需要 Ncr1，而 ThNK 细胞的抑制作用是通过 Klrk1 和穿孔素介导的。未来旨在增强再生的成功治疗方法将需要更深入地了解祖细胞免受 NK 细胞细胞毒性的保护。
