Reticular dysgenesis–associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress

• DOI: 10.1084/jem.20141286
• Publication Date: 2015-07-07T02:01:19Z
• Authors: Alberto Rissone; Katja Gabriele We...; Giancarlo la Marca; Kevin Bishop; Elisa Giocaliere; Jayashree Jagadeesh; Kerstin Felgentreff; Kerry Dobbs; Waleed Al-Herz; Marypat Jones; Settara Chandrase...; Martha Kirby; Stephen Wincovitch; Karen Lyn Simon; Yuval Itan; Alex DeVine; Thorsten Schlaeger; Axel Schambach; Raman Sood; Luigi D. Notarangelo; Fabio Candotti
• Keywords: Pluripotent Stem Cells; 570; Base Sequence; Reverse Transcriptase Polymerase Chain Reaction; Adenylate Kinase; Molecular Sequence Data; 610; Computational Biology; Apoptosis; Cell Differentiation; Leukopenia; Naphthalenes; Hematopoietic Stem Cells; Real-Time Polymerase Chain Reaction; Immunohistochemistry; Article; Acridine Orange; Antioxidants; 3. Good health; Oxidative Stress; Immunodeficiences; In Situ Nick-End Labeling; Animals; Azo Compounds; DNA Primers

Adenylate kinases (AKs) are phosphotransferases that regulate the cellular adenine nucleotide composition and play a critical role in energy homeostasis of all tissues. The AK2 isoenzyme is expressed mitochondrial intermembrane space mutated reticular dysgenesis (RD), rare form severe combined immunodeficiency (SCID) humans. RD characterized by maturation arrest myeloid lymphoid lineages, leading to early onset, recurrent, overwhelming infections. To gain insight into pathophysiology RD, we studied effects deficiency using zebrafish model induced pluripotent stem cells (iPSCs) derived from fibroblasts an patient. In zebrafish, Ak2 affected hematopoietic progenitor cell (HSPC) development with increased oxidative stress apoptosis. AK2-deficient iPSCs recapitulated characteristic at promyelocyte stage demonstrated AMP/ADP ratio, indicative energy-depleted profile. Antioxidant treatment rescued phenotypes vivo ak2 mutant restored differentiation mature granulocytes. Our results link fate depletion stress. This points potential use antioxidants as supportive therapeutic modality for patients RD.