title: Different origin of adipogenic stem cells influences the response to antiretroviral drugs.
abstract: Lipodystrophy (LD) is a main side effect of antiretroviral therapy for HIV infection, and can be provoked by nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs). LD exists in different forms, characterized by fat loss, accumulation, or both, but its pathogenesis is still unclear. In particular, few data exist concerning the effects of antiretroviral drugs on adipocyte differentiation. Adipose tissue can arise either from mesenchymal stem cells (MSCs), that include bone marrow-derived MSCs (hBM-MSCs), or from ectodermal stem cells, that include dental pulp stem cells (hDPSCs). To analyze whether the embryonal origin of adipocytes might impact the occurrence of different phenotypes in LD, we quantified the effects of several antiretroviral drugs on the adipogenic differentiation of hBM-MSCs and hDPSCs. hBM-MSCs and hDPSCs were isolated from healthy donors. Cells were treated with 10 and 50 μM stavudine (d4T), efavirenz (EFV), atazanavir (ATV), ritonavir (RTV), and ATV-boosted RTV. Viability and adipogenesis were evaluated by staining with propidium iodide, oil red, and adipoRed; mRNA levels of genes involved in adipocyte differentiation, i.e. CCAAT/enhancer-binding protein alpha (CEBPα) and peroxisome proliferator-activated receptor gamma (PPARγ), and in adipocyte functions, i.e. fatty acid synthase (FASN), fatty acid binding protein-4 (FABP4), perilipin-1 (PLIN1) and 1-acylglycerol-3-phosphate O-acyltransferase-2 (AGPAT2), were quantified by real time PCR. We found that ATV, RTV, EFV, and ATV-boosted RTV, but not d4T, caused massive cell death in both cell types. EFV and d4T affected the accumulation of lipid droplets and induced changes in mRNA levels of genes involved in adipocyte functions in hBM-MSCs, while RTV and ATV had little effects. All drugs stimulated the accumulation of lipid droplets in hDPSCs. Thus, the adipogenic differentiation of human stem cells can be influenced by antiretroviral drugs, and depends, at least in part, on their embryonal origin.
authors.affiliation: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia School of Medicine, Via Campi 287, 41125 Modena, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Gibellini
authors.affiliation: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia School of Medicine, Via Campi 287, 41125 Modena, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: De Biasi
authors.affiliation: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia School of Medicine, Via Campi 287, 41125 Modena, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Nasi
authors.affiliation: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia School of Medicine, Via Campi 287, 41125 Modena, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Carnevale
authors.affiliation: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia School of Medicine, Via Campi 287, 41125 Modena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pisciotta
authors.affiliation: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia School of Medicine, Via Campi 287, 41125 Modena, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Bianchini
authors.affiliation: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia School of Medicine, Via Campi 287, 41125 Modena, Italy.
authors.forename: Regina
authors.initials: R
authors.lastname: Bartolomeo
authors.affiliation: Department of Pharmacology, University of Valencia, Av.da Blasco Ibáñez 15, Valencia, Spain; FISABIO-Hospital Universitario Dr. Peset, Av.da Gaspar Aguilar 90, Valencia, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Polo
authors.affiliation: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia School of Medicine, Via Campi 287, 41125 Modena, Italy; Dipartimento Sperimentale Interaziendale, Campus San Lazzaro, University of Modena and Reggio Emilia, 42122 Reggio Emilia, Italy.
authors.forename: Anto
authors.initials: A
authors.lastname: De Pol
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Pinti
authors.affiliation: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia School of Medicine, Via Campi 287, 41125 Modena, Italy; Dipartimento Sperimentale Interaziendale, Campus San Lazzaro, University of Modena and Reggio Emilia, 42122 Reggio Emilia, Italy. Electronic address: andrea.cossarizza@unimore.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cossarizza
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000821:virology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D003782:Dental Pulp / Q000166:cytology / Q000187:drug effects* / Q000821:virology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000821:virology; D012190:Retroviridae / Q000187:drug effects*; D012192:Retroviridae Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology
chemical_list: D000998:Antiviral Agents
keywords: Antiretroviral drugs; Inhibitors; Lipodystrophy; Protease inhibitors; Reverse transcriptase