{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T10:02:45Z","timestamp":1766138565026,"version":"build-2065373602"},"reference-count":42,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T00:00:00Z","timestamp":1706486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health","award":["08052002\/13","080380\/14"],"award-info":[{"award-number":["08052002\/13","080380\/14"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>We previously published that in patients with infantile hemangioma (IH) at the onset (T0) colony forming unit-fibroblasts (CFU-Fs) are present in in vitro cultures from PB. Herein, we characterize these CFU-Fs and investigate their potential role in IH pathogenesis, before and after propranolol therapy. The CFU-F phenotype (by flow cytometry), their differentiation capacity and ability to support angiogenesis (by in vitro cultures) and their gene expression (by RT-PCR) were evaluated. We found that CFU-Fs are actual circulating MSCs (cMSCs). In patients at T0, cMSCs had reduced adipogenic potential, supported the formation of tube-like structures in vitro and showed either inflammatory (IL1\u03b2 and ESM1) or angiogenic (F3) gene expression higher than that of cMSCs from CTRLs. In patients receiving one-year propranolol therapy, the cMSC differentiation in adipocytes improved, while their support in in vitro tube-like formation was lost; no difference was found between patient and CTRL cMSC gene expressions. In conclusion, in patients with IH at T0 the cMSC reduced adipogenic potential, their support in angiogenic activity and the inflammatory\/angiogenic gene expression may fuel the tumor growth. One-year propranolol therapy modifies this picture, suggesting cMSCs as one of the drug targets.<\/jats:p>","DOI":"10.3390\/cells13030254","type":"journal-article","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T12:25:01Z","timestamp":1706531101000},"page":"254","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Circulating Mesenchymal Stromal Cells in Patients with Infantile Hemangioma: Evaluation of Their Functional Capacity and Gene Expression Profile"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4173-7055","authenticated-orcid":false,"given":"Carlotta","family":"Abb\u00e0","sequence":"first","affiliation":[{"name":"General Medicine 2\u2014Center for Systemic Amyloidosis and High-Complexity Diseases, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9176-4257","authenticated-orcid":false,"given":"Stefania","family":"Croce","sequence":"additional","affiliation":[{"name":"Immunology and Transplantation Laboratory, Cell Factory, Pediatric Haematology Oncology, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6103-2880","authenticated-orcid":false,"given":"Chiara","family":"Valsecchi","sequence":"additional","affiliation":[{"name":"Immunology and Transplantation Laboratory, Cell Factory, Pediatric Haematology Oncology, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Lenta","sequence":"additional","affiliation":[{"name":"Immunology and Transplantation Laboratory, Cell Factory, Pediatric Haematology Oncology, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4923-2761","authenticated-orcid":false,"given":"Rita","family":"Campanelli","sequence":"additional","affiliation":[{"name":"Center for the Study of Myelofibrosis, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessia C.","family":"Codazzi","sequence":"additional","affiliation":[{"name":"Pediatric Cardiology, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valeria","family":"Brazzelli","sequence":"additional","affiliation":[{"name":"Institute of Dermatology, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5254-8532","authenticated-orcid":false,"given":"Adriana","family":"Carolei","sequence":"additional","affiliation":[{"name":"Center for the Study of Myelofibrosis, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1862-8168","authenticated-orcid":false,"given":"Paolo","family":"Catarsi","sequence":"additional","affiliation":[{"name":"Center for the Study of Myelofibrosis, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gloria","family":"Acquafredda","sequence":"additional","affiliation":[{"name":"Immunology and Transplantation Laboratory, Cell Factory, Pediatric Haematology Oncology, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonia","family":"Apicella","sequence":"additional","affiliation":[{"name":"Pediatric Cardiology, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7545-7337","authenticated-orcid":false,"given":"Laura","family":"Caliogna","sequence":"additional","affiliation":[{"name":"Orthopedics and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Micaela","family":"Berni","sequence":"additional","affiliation":[{"name":"Orthopedics and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Savina","family":"Mannarino","sequence":"additional","affiliation":[{"name":"Pediatric Cardiology Unit, V. Buzzi Children\u2019s Hospital, 20154 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6056-9018","authenticated-orcid":false,"given":"Maria A.","family":"Avanzini","sequence":"additional","affiliation":[{"name":"Immunology and Transplantation Laboratory, Cell Factory, Pediatric Haematology Oncology, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4195-2289","authenticated-orcid":false,"given":"Vittorio","family":"Rosti","sequence":"additional","affiliation":[{"name":"Center for the Study of Myelofibrosis, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8037-0439","authenticated-orcid":false,"given":"Margherita","family":"Massa","sequence":"additional","affiliation":[{"name":"General Medicine 2\u2014Center for Systemic Amyloidosis and High-Complexity Diseases, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1542\/peds.2007-2767","article-title":"Growth characteristics of infantile hemangiomas: Implications for management","volume":"122","author":"Chang","year":"2008","journal-title":"Pediatrics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1097\/PRS.0b013e318208d2ac","article-title":"Untreated hemangiomas: Growth pattern and residual lesions","volume":"127","author":"Bauland","year":"2011","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/bjd.12435","article-title":"Pathogenesis of infantile haemangioma","volume":"169","author":"Greenberger","year":"2013","journal-title":"Br. J. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"38","DOI":"10.3389\/fsurg.2014.00038","article-title":"Biology of infantile hemangioma","volume":"1","author":"Itinteang","year":"2014","journal-title":"Front. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1097\/SCS.0b013e318193d6ac","article-title":"Progenitor cells in infantile hemangioma","volume":"20","author":"Bischoff","year":"2009","journal-title":"J. Craniofac. Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1017\/S146239940700052X","article-title":"Pathogenesis of infantile haemangioma: New molecular and cellular insights","volume":"9","author":"Ritter","year":"2007","journal-title":"Expert Rev. Mol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1634\/stemcells.2005-0298","article-title":"Mesenchymal stem cells and adipogenesis in hemangioma involution","volume":"24","author":"Yu","year":"2006","journal-title":"Stem Cells"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5","DOI":"10.2350\/11-01-0959-OA.1","article-title":"Mesenchymal stem cells in infantile hemangioma reside in the perivascular region","volume":"15","author":"Yuan","year":"2012","journal-title":"Pediatr. Dev. Pathol."},{"key":"ref_9","first-page":"2592","article-title":"Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice","volume":"118","author":"Khan","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1056\/NEJMoa1404710","article-title":"A randomized, controlled trial of oral propranolol in infantile hemangioma","volume":"372","author":"Hoeger","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Albi\u00f1ana, V., Gallardo-Vara, E., Casado-Vela, J., Recio-Poveda, L., Botella, L.M., and Cuesta, A.M. (2022). Propranolol: A \"Pick and Roll\" Team Player in Benign Tumors and Cancer Therapies. J. Clin. Med., 11.","DOI":"10.3390\/jcm11154539"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e5","DOI":"10.1097\/SAP.0000000000002104","article-title":"Propranolol Accelerats Hemangioma Stem Cell Transformation into Adipocyte","volume":"83","author":"Li","year":"2019","journal-title":"Ann. Plast. Surg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1055\/s-0038-1676855","article-title":"Kinetic and Angiogenic Activity of Circulating Endothelial Colony Forming Cells in Patients with Infantile Haemangioma Receiving Propranolol","volume":"119","author":"Campanelli","year":"2019","journal-title":"Thromb. Haemost."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6603","DOI":"10.1007\/s13277-015-3823-2","article-title":"Endothelial progenitor cells support tumour growth and metastatisation: Implications for the resistance to anti-angiogenic therapy","volume":"36","author":"Moccia","year":"2015","journal-title":"Tumour Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5802","DOI":"10.2174\/092986712804143240","article-title":"Store-dependent Ca(2+) entry in endothelial progenitor cells as a perspective tool to enhance cell-based therapy and adverse tumour vascularization","volume":"19","author":"Moccia","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1164\/rccm.200812-1949OC","article-title":"Circulating endothelial progenitor cells in preterm infants with bronchopulmonary dysplasia","volume":"180","author":"Borghesi","year":"2009","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.carpath.2015.02.005","article-title":"Circulating mesenchymal stem cells in patients with hypertrophic cardiomyopathy","volume":"24","author":"Marketou","year":"2015","journal-title":"Cardiovasc. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.msard.2019.08.013","article-title":"Circulating mesenchymal stem cells, stromal derived factor (SDF)-1 and IP-10 levels increased in clinically active multiple sclerosis patients but not in clinically stable patients treated with beta interferon","volume":"35","author":"Emamnejad","year":"2019","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Patry, C., Doniga, T., Lenz, F., Viergutz, T., Weiss, C., T\u00f6nshoff, B., Kalenka, A., Yard, B., Krebs, J., and Schaible, T. (2020). Increased mobilization of mesenchymal stem cells in patients with acute respiratory distress syndrome undergoing extracorporeal membrane oxygenation. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0227460"},{"key":"ref_20","first-page":"362","article-title":"Use of Some Additives for Improving Mesenchymal Stem Cell Isolation Outcomes in Non-Mobilized Peripheral Blood","volume":"21","author":"Pouryazdanpanah","year":"2018","journal-title":"Arch. Iran. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1186\/ar130","article-title":"Mesenchymal precursor cells in the blood of normal individuals","volume":"2","author":"Zvaifler","year":"2000","journal-title":"Arthritis Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1002\/jat.3819","article-title":"In vitro toxicity screening of magnetite nanoparticles by applying mesenchymal stem cells derived from human umbilical cord lining","volume":"39","author":"Coccini","year":"2019","journal-title":"J. Appl. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1111\/bjh.13504","article-title":"Comprehensive characterization of mesenchymal stromal cells from patients with Fanconi anaemia","volume":"170","author":"Mantelli","year":"2015","journal-title":"Br. J. Haematol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/jcp.20911","article-title":"Optimization of in vitro expansion of human multipotent mesenchymal stromal cells for cell-therapy approaches: Further insights in the search for a fetal calf serum substitute","volume":"211","author":"Bernardo","year":"2007","journal-title":"J. Cell Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1080\/14653240600855905","article-title":"Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement","volume":"8","author":"Dominici","year":"2006","journal-title":"Cytotherapy"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1016\/j.jcyt.2013.06.006","article-title":"Genomic alterations in human umbilical cord-derived mesenchymal stromal cells call for stringent quality control before any possible therapeutic approach","volume":"15","author":"Borghesi","year":"2013","journal-title":"Cytotherapy"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1002\/sctm.19-0044","article-title":"Challenges in Clinical Development of Mesenchymal Stromal\/Stem Cells: Concise Review","volume":"8","author":"Mastrolia","year":"2019","journal-title":"Stem Cells Trans. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1684\/ejd.2023.4484","article-title":"Propranolol for the treatment of infantile hemangiomas: A nine-year monocentric experience from a tertiary hospital","volume":"33","author":"Codazzi","year":"2023","journal-title":"Eur. J. Dermatol. EJD"},{"key":"ref_29","unstructured":"Hall, B., Andreeff, M., and Marini, F. (2007). Handbook of Experimental Pharmacology, Springer."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.earlhumdev.2012.12.006","article-title":"Circulating hematopoietic and endothelial progenitor cells in newborn infants: Effects of gestational age, postnatal age and clinical stress in the first 3 weeks of life","volume":"89","author":"Bui","year":"2013","journal-title":"Early Hum. Dev."},{"key":"ref_31","first-page":"48","article-title":"Propranolol inhibits angiogenesis via down-regulating the expression of vascular endothelial growth factor in hemangioma derived stem cell","volume":"7","author":"Zhang","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_32","first-page":"3809","article-title":"Propranolol enhanced adipogenesis instead of induction of apoptosis of hemangiomas stem cells","volume":"7","author":"Ma","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S119","DOI":"10.1097\/SAP.0000000000000272","article-title":"Propranolol promotes accelerated and dysregulated adipogenesis in hemangioma stem cells","volume":"73","author":"England","year":"2014","journal-title":"Ann. Plast. Surg."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1097\/PRS.0b013e318267d3db","article-title":"Propranolol accelerates adipogenesis in hemangioma stem cells and causes apoptosis of hemangioma endothelial cells","volume":"130","author":"Wong","year":"2012","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1080\/08880018.2021.1961956","article-title":"Vascular endothelial growth factor response with propranolol therapy in patients with infantile hemangioma","volume":"39","author":"Makkeyah","year":"2022","journal-title":"Pediatr. Hematol. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Yuan, W., and Wang, X. (2021). Propranolol Participates in the Treatment of Infantile Hemangioma by Inhibiting HUVECs Proliferation, Migration, Invasion, and Tube Formation. Biomed. Res. Int., 2021.","DOI":"10.1155\/2021\/6636891"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"687120","DOI":"10.3389\/fonc.2021.687120","article-title":"Targeting Endothelial Cell-Specific Molecule 1 Protein in Cancer: A Promising Therapeutic Approach","volume":"11","author":"Zhang","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1160\/TH16-07-0524","article-title":"mCRP triggers angiogenesis by inducing F3 transcription and TF signalling in microvascular endothelial cells","volume":"117","author":"Arderiu","year":"2017","journal-title":"Thromb. Haemost."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1530\/JOE-21-0187","article-title":"Vascular reactivity contributes to adipose tissue remodeling in obesity","volume":"251","author":"Lee","year":"2021","journal-title":"J. Endocrinol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1111\/1346-8138.16781","article-title":"Analysis of cytokine profiles in sera of single and multiple infantile hemangioma","volume":"50","author":"Sakata","year":"2023","journal-title":"J. Dermatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1007\/s10517-023-05745-x","article-title":"Changes Induced by Inflammatory-Activated Immune Cell Microenvironment in the Paracrine Profile of MSC","volume":"174","author":"Gornostaeva","year":"2023","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Barra, J., Cerda-Infante, J., Sandoval, L., Gajardo-Meneses, P., Henriquez, J.F., Labarca, M., Metz, C., Venegas, J., Retamal, C., and Oyanadel, C. (2021). D-Propranolol Impairs EGFR Trafficking and Destabilizes Mutant p53 Counteracting AKT Signaling and Tumor Malignancy. Cancers, 13.","DOI":"10.3390\/cancers13143622"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/3\/254\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:51:23Z","timestamp":1760104283000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/3\/254"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,29]]},"references-count":42,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["cells13030254"],"URL":"https:\/\/doi.org\/10.3390\/cells13030254","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2024,1,29]]}}}