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| Pàgina inicial > Articles > Articles publicats > Upregulation of NKG2D ligands impairs hematopoietic stem cell function in Fanconi anemia |
(Centro de Investigación Biomédica en Red de Enfermedades Raras) (Centro de Investigación Biomédica en Red de Enfermedades Raras) (Institut d'Investigació Biomèdica Sant Pau) (Institut d'Investigació Biomèdica Sant Pau) (Centro de Investigación Biomédica en Red de Enfermedades Raras)| Data: | 2022 |
| Resum: | Fanconi anemia (FA) is the most prevalent inherited bone marrow failure (BMF) syndrome. Nevertheless, the pathophysiological mechanisms of BMF in FA have not been fully elucidated. Since FA cells are defective in DNA repair, we hypothesized that FA hematopoietic stem and progenitor cells (HSPCs) might express DNA damage-associated stress molecules such as natural killer group 2 member D ligands (NKG2D-Ls). These ligands could then interact with the activating NKG2D receptor expressed in cytotoxic NK or CD8+ T cells, which may result in progressive HSPC depletion. Our results indeed demonstrated upregulated levels of NKG2D-Ls in cultured FA fibroblasts and T cells, and these levels were further exacerbated by mitomycin C or formaldehyde. Notably, a high proportion of BM CD34+ HSPCs from patients with FA also expressed increased levels of NKG2D-Ls, which correlated inversely with the percentage of CD34+ cells in BM. Remarkably, the reduced clonogenic potential characteristic of FA HSPCs was improved by blocking NKG2D-NKG2D-L interactions. Moreover, the in vivo blockage of these interactions in a BMF FA mouse model ameliorated the anemia in these animals. Our study demonstrates the involvement of NKG2D-NKG2D-L interactions in FA HSPC functionality, suggesting an unexpected role of the immune system in the progressive BMF that is characteristic of FA. |
| Ajuts: | European Commission HEALTHF5-2012-305421 Ministerio de Economía y Competitividad SAF2015-68073-R Ministerio de Economía y Competitividad SAF2015-64152-R Agencia Estatal de Investigación RTI2018-097125-B-I00 Instituto de Salud Carlos III RD12/0019/0023 Ministerio de Sanidad EC11/060 Ministerio de Sanidad EC11/550 |
| Nota: | Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER); Next Generation EU; EUROFANCOLEN); Comunidad de Madrid (AvanCell, B2017/BMD-3692); ICREA-Academia program. |
| Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | Animals ; Antigens, CD34 ; Fanconi Anemia ; Hematopoietic Stem Cells ; Ligands ; Mice ; NK Cell Lectin-Like Receptor Subfamily K ; Up-Regulation |
| Publicat a: | The journal of clinical investigation, Vol. 132 Núm. 15 (january 2022) , p. e142842, ISSN 1558-8238 |
