1. Impact of lysosomal storage disorders on biology of mesenchymal stem cells: Evidences from in vitro silencing of glucocerebrosidase (GBA) and alpha-galactosidase A (GLA) enzymes
- Author
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Ivana Antonucci, Tiziana Squillaro, Liborio Stuppia, Mariarosa A. B. Melone, Umberto Galderisi, Marilena Cipollaro, Nicola Alessio, Anna Esposito, Gianfranco Peluso, Squillaro, Tiziana, Antonucci, Ivana, Alessio, Nicola, Esposito, Anna, Cipollaro, Marilena, Melone, Mariarosa Anna Beatrice, Peluso, Gianfranco, Stuppia, Liborio, Galderisi, Umberto, Squillaro, T, Antonucci, I, Alessio, N, Esposito, A, Peluso, G, and Stuppia, L
- Subjects
0301 basic medicine ,senescence ,DNA Repair ,Physiology ,Clinical Biochemistry ,Apoptosis ,Cell Separation ,Gene mutation ,Retinoblastoma Protein ,0302 clinical medicine ,Stem Cell Niche ,Child ,mesenchymal stem cell ,Cells, Cultured ,Cellular Senescence ,education.field_of_study ,Cell biology ,Haematopoiesis ,030220 oncology & carcinogenesis ,S Phase Cell Cycle Checkpoint ,S Phase Cell Cycle Checkpoints ,Bone Marrow Cell ,Glucosylceramidase ,lysosomal storage disorder ,Female ,RNA Interference ,Stem cell ,Human ,Signal Transduction ,Senescence ,autophagy, fabry disease, gaucher disease, lysosomal storage disorders, mesenchymal stemcells, senescence ,DNA repair ,Population ,Bone Marrow Cells ,Biology ,Transfection ,lysosomal storage disorders ,mesenchymal stemcells ,03 medical and health sciences ,Autophagy ,Humans ,education ,Gaucher Disease ,Mesenchymal stem cell ,Apoptosi ,Mesenchymal Stem Cells ,Cell Biology ,Amniotic Fluid ,030104 developmental biology ,alpha-Galactosidase ,Immunology ,Fabry Disease ,Tumor Suppressor Protein p53 ,Glucocerebrosidase - Abstract
Lysosomal storage disorders (LDS) comprise a group of rare multisystemic diseases resulting from inherited gene mutations that impair lysosomal homeostasis. The most common LSDs, Gaucher disease (GD) and Fabry disease (FD) are caused by deficiencies in the lysosomal glucocerebrosidase (GBA) and alpha-galactosidase A (GLA) enzymes, respectively. Given the systemic nature of enzyme deficiency, we hypothesized that the stem cell compartment of GD and FD patients might be also affected. Among stem cells, mesenchymal stem cells (MSCs) are a commonly investigated population given their role in hematopoiesis and the homeostatic maintenance of many organs and tissues. Since the impairment of MSC functions could pose profound consequences on body physiology, we evaluated whether GBA and GLA silencing could affect the biology of MSCs isolated from bone marrow and amniotic fluid. Those cell populations were chosen given the former's key role in organ physiology and the latter's intriguing potential as an alternative stem cell model for human genetic disease. Our results revealed that GBA and GLA deficiencies prompted cell cycle arrest along with the impairment of autophagic flux and an increase of apoptotic and senescence cell percentages. Moreover, an increase in ataxia–telangiectasia-mutated staining 1 h after oxidative stress induction and a return to basal level at 48 h, along with persistent gamma-H2AX staining, indicated that MSCs properly activated DNA repair signaling, though some damages remained unrepaired. Our data therefore suggest that MSCs with reduced GBA or GLA activity are prone to apoptosis and senescence due to impaired autophagy and DNA repair capacity. This article is protected by copyright. All rights reserved
- Published
- 2016