Impact of Progerin Expression on Adipogenesis in Hutchinson—Gilford Progeria Skin-Derived Precursor Cells

Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is a segmental premature aging disease caused by a mutation in LMNA. The mutation generates a truncated and farnesylated form of prelamin A, called progerin. Affected individuals develop several features of normal aging, including lipodystrophy caused by the loss of general subcutaneous fat. To determine whether premature cellular senescence is responsible for the altered adipogenesis in patients with HGPS, we evaluated the differentiation of HGPS skin-derived precursor stem cells (SKPs) into adipocytes. The SKPs were isolated from primary human HGPS and normal fibroblast cultures, with senescence of 5 and 30%. We observed that the presence of high numbers of senescent cells reduced SKPs’ adipogenic differentiation potential. Treatment with baricitinib, a JAK–STAT inhibitor, ameliorated the ability of HGPS SKPs to differentiate into adipocytes. Our findings suggest that the development of lipodystrophy in patients with HGPS may be associated with an increased rate of cellular senescence and chronic inflammation.

Impact of Combined Baricitinib and FTI Treatment on Adipogenesis in Hutchinson–Gilford Progeria Syndrome and Other Lipodystrophic Laminopathies

“…The cells were cultured in adipocyte differentiation media (ADM) consisting of DMEM supplemented with 4.5 g/L glucose (Thermo Fisher-Gibco, 21885025), 0.5 mM 3-isobutyl-1-methylxanthine (IBMX, Sigma-Aldrich, St., Louis, MO, USA, I7018, stock in absolute ethanol (VWR chemicals, Radnor, PA, USA, 20821.33)), 10 µg/mL insulin (Sigma-Aldrich, I2643, stock in 0.01 M HCL [Merck KGaA, 1.00319.2500] in Ultra-Pure water from MilliQ [MQ]), 100 µM L-Ascorbic Acid (Sigma-Aldrich, A8960, stock in Ultra-Pure water from MilliQ [MQ]), 1 µM dexamethasone (Sigma-Aldrich, D4902 (stock in absolute ethanol)), 10% FBS, 0.5 µg/mL fungizone, 50 µM indomethacin (Sigma-Aldrich, I7378, stock in 100% DMSO [Sigma-Aldrich, D2650]), and 100 U/100 µg/mL penicillin/streptomycin. The media was replaced every 2-3 d [58].…”

“…Previous studies have successfully isolated SKP spheroids from primary fibroblast cultures using the low-pH stress method [57]. Senescence plays an important role in SKP differentiation [58]; therefore, young fibroblast cultures with <5% senescence rate were used for the analysis to prevent the effect of age on the differentiation potential of SKPs. The SKP isolation method is illustrated in Figure 1.…”

“…Specifically, we examined the effect of combined treatment with Bar and lonafarnib on adipogenesis in cells derived from patients with HGPS, FPLD2, and MADB. An ex vivo cellular model consisting of skin-derived precursors (SKPs) isolated from human primary fibroblast HGPS, FPLD2, and MADB was established using the pHstress method [57,58]. Multipotent SKPs are found in adult human skin and express stem cell markers [59][60][61].…”

Molecular and Cellular Bases of Lipodystrophy Syndromes

“…Clinical features of accelerated ageing are observed in patients with complex progeroid forms of LMNA-linked lipodystrophies, with a large continuum of severity between Dunnigan syndrome and Hutchinson-Gilford progeria (67,71). At the cellular level, LMNA pathogenic variants impair the fate of several mesodermal lineages, such as endothelial vascular cells (64), myoblasts (95), cardiomyocytes (96), and adipocytes (97)(98)(99)(100)(101), and are involved in several signaling pathways which accelerate aging processes (102,103).…”

Regulation of Lipid Metabolism by Lamin in Mutation-Related Diseases

“…Moreover, progerin, a farnylated protein resulting from LMNA mutation, can harden the nucleus and reduce the reorganization, finally wiping the differentiation of lipocytes. Lipid accumulation happens, while low progerin expresses (Najdi et al, 2021). In short, targeting progerin may be an effective method to improve lipid disorders.…”