{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T13:48:20Z","timestamp":1791726500342,"version":"4.3.4"},"reference-count":48,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,30]],"date-time":"2020-12-30T00:00:00Z","timestamp":1609286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Madelung Disease (MD) is a syndrome characterized by the accumulation of aberrant symmetric adipose tissue deposits. The etiology of this disease is yet to be elucidated, even though the presence of comorbidities, either genetic or environmental, has been reported. For this reason, establishing an in vitro model for MD is considered crucial to get insights into its physiopathology. We previously established a protocol for isolation and culture of stem cells from diseased tissues. Therefore, we isolated human adipose-derived stem cells (ASC) from MD patients and compared these cells with those isolated from healthy subjects in terms of surface phenotype, growth kinetic, adipogenic differentiation potential, and molecular alterations. Moreover, we evaluated the ability of the MD-ASC secretome to affect healthy ASC. The results reported a difference in the growth kinetic and surface markers of MD-ASC compared to healthy ASC but not in adipogenic differentiation. The most commonly described mitochondrial mutations were not observed. Still, MD-ASC secretome was able to shift the healthy ASC phenotype to an MD phenotype. This work provides evidence of the possibility of exploiting a patient-based in vitro model for better understanding MD pathophysiology, possibly favoring the development of novel target therapies.<\/jats:p>","DOI":"10.3390\/cells10010044","type":"journal-article","created":{"date-parts":[[2020,12,30]],"date-time":"2020-12-30T20:13:41Z","timestamp":1609359221000},"page":"44","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Human Adipose-Derived Stem Cells in Madelung\u2019s Disease: Morphological and Functional Characterization"],"prefix":"10.3390","volume":"10","author":[{"given":"Federica","family":"Caponnetto","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Manini","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2646-4228","authenticated-orcid":false,"given":"Michela","family":"Bulfoni","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1575-0029","authenticated-orcid":false,"given":"Nicola","family":"Zingaretti","sequence":"additional","affiliation":[{"name":"Department of Medical Area (DAME), Clinic of Plastic and Reconstructive Surgery, Academic Hospital of Udine, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Miotti","sequence":"additional","affiliation":[{"name":"Department of Medical Area (DAME), Clinic of Plastic and Reconstructive Surgery, Academic Hospital of Udine, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Di Loreto","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"},{"name":"Institute of Pathology, University Hospital of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0562-7852","authenticated-orcid":false,"given":"Daniela","family":"Cesselli","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"},{"name":"Institute of Pathology, University Hospital of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Mariuzzi","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"},{"name":"Institute of Pathology, University Hospital of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pier Camillo","family":"Parodi","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"},{"name":"Department of Medical Area (DAME), Clinic of Plastic and Reconstructive Surgery, Academic Hospital of Udine, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/S0953-6205(00)00086-8","article-title":"Benign Symmetric Lipomatosis (Madelung\u2019s Disease)","volume":"11","author":"Iglesias","year":"2000","journal-title":"Eur. J. Intern. Med."},{"key":"ref_2","first-page":"108","article-title":"Benign Symmetric Lipomatosis (Madelung\u2019s Disease): Case Reports and Current Management","volume":"28","year":"2004","journal-title":"Aesth. Plast. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S66","DOI":"10.1097\/SAP.0000000000001719","article-title":"Madelung Disease: Analysis of Clinicopathological Experience in Taipei Veterans General Hospital","volume":"82","author":"Wan","year":"2019","journal-title":"Ann. Plast. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6570","DOI":"10.3892\/mmr.2017.7437","article-title":"Profiling of Differentially Expressed Genes in Adipose Tissues of Multiple Symmetric Lipomatosis","volume":"16","author":"Chen","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"819","DOI":"10.2147\/DMSO.S181154","article-title":"Madelung\u2019s Disease\u2014Progressive, Excessive, and Symmetrical Deposition of Adipose Tissue in the Subcutaneous Layer: Case Report and Literature Review","volume":"11","author":"Szewc","year":"2018","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_6","unstructured":"Feingold, K.R., Anawalt, B., Boyce, A., Chrousos, G., de Herder, W.W., Dungan, K., Grossman, A., Hershman, J.M., Hofland, H.J., and Kaltsas, G. (2000). Subcutaneous Adipose Tissue Diseases: Dercum Disease, Lipedema, Familial Multiple Lipomatosis, and Madelung Disease. Endotext, MDText.com, Inc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1007\/s00266-020-01666-6","article-title":"Adipose Tissue in Multiple Symmetric Lipomatosis Shows Features of Brown\/Beige Fat","volume":"44","author":"Schiltz","year":"2020","journal-title":"Aesthetic Plast. Surg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.numecd.2015.01.010","article-title":"Multiple Symmetric Lipomatosis: A Rare Disease and Its Possible Links to Brown Adipose Tissue","volume":"25","author":"Enzi","year":"2015","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8444","DOI":"10.1038\/s41598-019-44382-1","article-title":"Calcyphosine-like (CAPSL) Is Regulated in Multiple Symmetric Lipomatosis and Is Involved in Adipogenesis","volume":"9","author":"Lindner","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"11909","DOI":"10.1038\/srep11909","article-title":"MiR-125a-3p and MiR-483-5p Promote Adipogenesis via Suppressing the RhoA\/ROCK1\/ERK1\/2 Pathway in Multiple Symmetric Lipomatosis","volume":"5","author":"Chen","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"35989","DOI":"10.1074\/jbc.M111.254201","article-title":"Identification of a Cytochrome P4502E1\/Bid\/C1q-Dependent Axis Mediating Inflammation in Adipose Tissue after Chronic Ethanol Feeding to Mice","volume":"286","author":"Sebastian","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/ng1642","article-title":"Lymphatic Vascular Defects Promoted by Prox1 Haploinsufficiency Cause Adult-Onset Obesity","volume":"37","author":"Harvey","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1023\/A:1006877012241","article-title":"Mitochondrial DNA Mutations in Multiple Symmetric Lipomatosis","volume":"174","author":"Klopstock","year":"1997","journal-title":"Mol. Cell. Biochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1212\/WNL.44.5.862","article-title":"Multiple Symmetric Lipomatosis: Abnormalities in Complex IV and Multiple Deletions in Mitochondrial DNA","volume":"44","author":"Klopstock","year":"1994","journal-title":"Neurology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5109","DOI":"10.1093\/hmg\/ddv229","article-title":"Homozygous Mutations in MFN2 Cause Multiple Symmetric Lipomatosis Associated with Neuropathy","volume":"24","author":"Sawyer","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1002\/ajmg.a.37880","article-title":"Homozygous LIPE Mutation in Siblings with Multiple Symmetric Lipomatosis, Partial Lipodystrophy, and Myopathy","volume":"173","author":"Zolotov","year":"2017","journal-title":"Am. J. Med. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/1750-1172-8-34","article-title":"A Human Neuronal Model of Niemann Pick C Disease Developed from Stem Cells Isolated from Patient\u2019s Skin","volume":"8","author":"Bergamin","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1002\/stem.1605","article-title":"Glioma-Associated Stem Cells: A Novel Class of Tumor-Supporting Cells Able to Predict Prognosis of Human Low-Grade Gliomas","volume":"32","author":"Bourkoula","year":"2014","journal-title":"Stem Cells"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Manini, I., Ruaro, M.E., Sgarra, R., Bartolini, A., Caponnetto, F., Ius, T., Skrap, M., Di Loreto, C., Beltrami, A.P., and Manfioletti, G. (2019). Semaphorin-7A on Exosomes: A Promigratory Signal in the Glioma Microenvironment. Cancers, 11.","DOI":"10.3390\/cancers11060758"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e81","DOI":"10.1161\/CIRCRESAHA.115.306146","article-title":"Combined Intramyocardial Delivery of Human Pericytes and Cardiac Stem Cells Additively Improves the Healing of Mouse Infarcted Hearts through Stimulation of Vascular and Muscular Repair","volume":"116","author":"Avolio","year":"2015","journal-title":"Circ. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.1002\/stem.1728","article-title":"Ex Vivo Molecular Rejuvenation Improves the Therapeutic Activity of Senescent Human Cardiac Stem Cells in a Mouse Model of Myocardial Infarction","volume":"32","author":"Avolio","year":"2014","journal-title":"Stem Cells"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1093\/neuonc\/nox234","article-title":"An NF-\u039aB Signature Predicts Low-Grade Glioma Prognosis: A Precision Medicine Approach Based on Patient-Derived Stem Cells","volume":"20","author":"Ius","year":"2018","journal-title":"Neuro Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/scrt536","article-title":"Adipose Tissue Derived Stem Cells: In Vitro and in Vivo Analysis of a Standard and Three Commercially Available Cell-Assisted Lipotransfer Techniques","volume":"6","author":"Domenis","year":"2015","journal-title":"Stem Cell Res. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"451","DOI":"10.3109\/02713683.2012.763100","article-title":"Human Adipose-Derived Stem Cells for the Treatment of Chemically Burned Rat Cornea: Preliminary Results","volume":"38","author":"Zeppieri","year":"2013","journal-title":"Curr. Eye Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Domenis, R., Bergamin, N., Gianfranceschi, G., Vascotto, C., Romanello, M., Rigo, S., Vagnarelli, G., Faggiani, M., Parodi, P., and Kelley, M.R. (2014). The Redox Function of APE1 Is Involved in the Differentiation Process of Stem Cells toward a Neuronal Cell Fate. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0089232"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Al-Ghadban, S., Diaz, Z.T., Singer, H.J., Mert, K.B., and Bunnell, B.A. (2020). Increase in Leptin and PPAR-\u03b3 Gene Expression in Lipedema Adipocytes Differentiated in Vitro from Adipose-Derived Stem Cells. Cells, 9.","DOI":"10.3390\/cells9020430"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Al-Ghadban, S., Pursell, I.A., Diaz, Z.T., Herbst, K.L., and Bunnell, B.A. (2020). 3D Spheroids Derived from Human Lipedema ASCs Demonstrated Similar Adipogenic Differentiation Potential and ECM Remodeling to Non-Lipedema ASCs In Vitro. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218350"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3438","DOI":"10.1182\/blood-2006-11-055566","article-title":"Multipotent Cells Can Be Generated in Vitro from Several Adult Human Organs (Heart, Liver, and Bone Marrow)","volume":"110","author":"Beltrami","year":"2007","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/13779","article-title":"Reanalysis and Revision of the Cambridge Reference Sequence for Human Mitochondrial DNA","volume":"23","author":"Andrews","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_30","first-page":"400","article-title":"Madelung Disease","volume":"5","author":"Lewicki","year":"2015","journal-title":"Postep. Derm. Alergol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"397","DOI":"10.4048\/jbc.2014.17.4.397","article-title":"Multiple Symmetric Lipomatosis (Madelung\u2019s Disease) Presenting as Bilateral Huge Gynecomastia","volume":"17","author":"Jang","year":"2014","journal-title":"J. Breast Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2490","DOI":"10.1002\/term.2147","article-title":"Characterization of Human Adipose Tissue-Derived Stem Cells with Enhanced Angiogenic and Adipogenic Properties","volume":"11","author":"Lauvrud","year":"2017","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/aps.2011.153","article-title":"Rare Adipose Disorders (RADs) Masquerading as Obesity","volume":"33","author":"Herbst","year":"2012","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_34","unstructured":"(2020, October 14). Mitochondrial Dysfunction in Multiple Symmetrical Lipomatosis\u2014PubMed, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/1650162\/."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1111\/cge.13701","article-title":"Mitochondrial DNA Pathogenic Mutations in Multiple Symmetric Lipomatosis","volume":"97","author":"Emperador","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_36","unstructured":"(2020, October 14). Lipomatosis Incidence and Characteristics in an Italian Cohort of Mitochondrial Patients\u2014PubMed, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/30873109\/."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"204173141559235","DOI":"10.1177\/2041731415592356","article-title":"Isolation of Adipose and Bone Marrow Mesenchymal Stem Cells Using CD29 and CD90 Modifies Their Capacity for Osteogenic and Adipogenic Differentiation","volume":"6","author":"Davies","year":"2015","journal-title":"J. Tissue Eng."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1159\/000444501","article-title":"Adipose-Derived Stromal Cells from Lipomas: Isolation, Characterisation and Review of the Literature","volume":"83","author":"Tremp","year":"2016","journal-title":"Pathobiology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s00424-007-0285-4","article-title":"Role of CD9 in Proliferation and Proangiogenic Action of Human Adipose-Derived Mesenchymal Stem Cells","volume":"455","author":"Kim","year":"2007","journal-title":"Pflugers Arch. Eur. J. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2681","DOI":"10.1038\/s41418-020-0537-9","article-title":"CD9 Induces Cellular Senescence and Aggravates Atherosclerotic Plaque Formation","volume":"27","author":"Cho","year":"2020","journal-title":"Cell Death Differ."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.bbrc.2012.05.134","article-title":"Increased Stemness and Migration of Human Mesenchymal Stem Cells in Hypoxia Is Associated with Altered Integrin Expression","volume":"423","author":"Saller","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2754","DOI":"10.18632\/aging.101082","article-title":"Aging Is Associated with an Expansion of CD49fhi Mammary Stem Cells That Show a Decline in Function and Increased Transformation Potential","volume":"8","author":"Dong","year":"2016","journal-title":"Aging (Albany NY)"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/s10735-007-9128-z","article-title":"Selection Using the Alpha-1 Integrin (CD49a) Enhances the Multipotentiality of the Mesenchymal Stem Cell Population from Heterogeneous Bone Marrow Stromal Cells","volume":"38","author":"Rider","year":"2007","journal-title":"J. Mol. Histol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3175748","DOI":"10.1155\/2017\/3175748","article-title":"Different Angiogenic Potentials of Mesenchymal Stem Cells Derived from Umbilical Artery, Umbilical Vein, and Wharton\u2019s Jelly","volume":"2017","author":"Xu","year":"2017","journal-title":"Stem Cells Int."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1126\/science.284.5411.143","article-title":"Multilineage Potential of Adult Human Mesenchymal Stem Cells","volume":"284","author":"Pittenger","year":"1999","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Stojanovi\u0107, S., Najman, S., and Kora\u0107, A. (2018). Stem Cells Derived from Lipoma and Adipose Tissue\u2014Similar Mesenchymal Phenotype but Different Differentiation Capacity Governed by Distinct Molecular Signature. Cells, 7.","DOI":"10.3390\/cells7120260"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2019\/1609876","article-title":"Comparison of Properties of Stem Cells Isolated from Adipose Tissue and Lipomas in Dogs","volume":"2019","author":"Teshima","year":"2019","journal-title":"Stem Cells Int."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.ajpath.2011.03.036","article-title":"Effects of Age and Heart Failure on Human Cardiac Stem Cell Function","volume":"179","author":"Cesselli","year":"2011","journal-title":"Am. J. Pathol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/1\/44\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:48:07Z","timestamp":1760179687000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/1\/44"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,30]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["cells10010044"],"URL":"https:\/\/doi.org\/10.3390\/cells10010044","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,30]]}}}