Thromb Haemost 2019; 119(02): 274-284
DOI: 10.1055/s-0038-1676855
Endothelium and Angiogenesis
Georg Thieme Verlag KG Stuttgart · New York

Kinetic and Angiogenic Activity of Circulating Endothelial Colony Forming Cells in Patients with Infantile Haemangioma Receiving Propranolol

Rita Campanelli*
1   Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnosis, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
,
Alessia Claudia Codazzi*
2   Cardiology Clinic of Pediatrics, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
,
Valentina Poletto
1   Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnosis, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
,
Carlotta Abbà
1   Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnosis, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
,
Paolo Catarsi
1   Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnosis, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
,
Gabriela Fois
1   Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnosis, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
,
Maria Antonietta Avanzini
3   Immunology and Transplantation Laboratory/Cell Factory/Pediatric Haematology/Oncology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
,
Valeria Brazzelli
4   Department of Clinical-Surgical, Diagnostic and Pediatric Science, Institute of Dermatology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
,
Chryssoula Tzialla
5   Neonatal Intensive Care Unit, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
,
Annalisa De Silvestri
6   Epidemiology Service, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
,
Carmine Tinelli
6   Epidemiology Service, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
,
Amelia Licari
7   Department of Pediatrics, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy
,
Roberto Berra-Romani
8   Department of Biomedicine, School of Medicine, Benemérita Universidad Autónoma de Puebla, Puebla, México
,
Estella Zuccolo
9   Laboratory of General Physiology, Department of Biology and Biotechnology “Lazzaro Spallanzani,” University of Pavia, Pavia, Italy
,
Francesco Moccia
9   Laboratory of General Physiology, Department of Biology and Biotechnology “Lazzaro Spallanzani,” University of Pavia, Pavia, Italy
,
Savina Mannarino
2   Cardiology Clinic of Pediatrics, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
,
Vittorio Rosti
1   Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnosis, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
,
Margherita Massa
10   Laboratory of Biochemistry, Biotechnology and Advanced Diagnosis, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
› Institutsangaben
Funding The present project was financially supported by the intramural funding program “Ricerca Corrente” of the IRCCS Policlinico San Matteo Foundation: RC/80520 to M. Massa.
Weitere Informationen

Publikationsverlauf

18. Juli 2018

15. November 2018

Publikationsdatum:
04. Januar 2019 (online)

Abstract

Endothelial progenitor cells (EPCs) have been suggested to contribute to the neovascularization of infantile haemangioma (IH). There is strong evidence of the efficacy of propranolol in the treatment of IH, possibly by inhibiting both vasculogenesis and angiogenesis in the tumour. We evaluate the frequency of circulating endothelial colony forming cells (ECFCs), as the best EPC surrogate, in patients with IH at diagnosis and while receiving propranolol by an ex vivo 12-month longitudinal study. Biological aspects of the ECFCs, such as their in vitro angiogenic potential, membrane CXCR4 expression and Ca2+ signalling, were investigated. Circulating ECFCs were isolated by in vitro culture and expanded for 2 to 3 passages in 23 patients with IH (median age: 5.5 months, range: 5.5 weeks–11 months) before and 3, 6, 9 and 12 months after receiving propranolol. Twenty-four healthy subjects comparable for age were also assessed (CTRLs). Untreated patients with IH had a circulating ECFC frequency lower (p = 0.001) than CTRLs; nevertheless, in in vitro starving conditions, ECFCs showed enhanced capacity to form tube-like structures than those of CTRLs. Patients with IH following the therapy with propranolol had a significantly increased (p = 0.022) circulating ECFC frequency, that showed a diminished tube-like formation capacity in vitro, and an altered constitutive store-operated Ca2+ entry. ECFCs play a role in IH pathogenesis; the response to propranolol therapy is associated with their increased frequency in the peripheral blood and a reduction of their vasculogenic activity.

* These authors equally contributed to the manuscript.


Supplementary Material

 
  • References

  • 1 Chang LC, Haggstrom AN, Drolet BA. , et al; Hemangioma Investigator Group. Growth characteristics of infantile hemangiomas: implications for management. Pediatrics 2008; 122 (02) 360-367
  • 2 Bauland CG, Lüning TH, Smit JM, Zeebregts CJ, Spauwen PH. Untreated hemangiomas: growth pattern and residual lesions. Plast Reconstr Surg 2011; 127 (04) 1643-1648
  • 3 Greenberger S, Bischoff J. Pathogenesis of infantile haemangioma. Br J Dermatol 2013; 169 (01) 12-19
  • 4 Boye E, Yu Y, Paranya G, Mulliken JB, Olsen BR, Bischoff J. Clonality and altered behavior of endothelial cells from hemangiomas. J Clin Invest 2001; 107 (06) 745-752
  • 5 Khan ZA, Melero-Martin JM, Wu X. , et al. Endothelial progenitor cells from infantile hemangioma and umbilical cord blood display unique cellular responses to endostatin. Blood 2006; 108 (03) 915-921
  • 6 Kleinman ME, Tepper OM, Capla JM. , et al. Increased circulating AC133+ CD34+ endothelial progenitor cells in children with hemangioma. Lymphat Res Biol 2003; 1 (04) 301-307
  • 7 Zaccone V, Flore R, Santoro L. , et al. Focus on biological identity of endothelial progenitors cells. Eur Rev Med Pharmacol Sci 2015; 19 (21) 4047-4063
  • 8 Ingram DA, Mead LE, Tanaka H. , et al. Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood 2004; 104 (09) 2752-2760
  • 9 Case J, Mead LE, Bessler WK. , et al. Human CD34+AC133+VEGFR-2+ cells are not endothelial progenitor cells but distinct, primitive hematopoietic progenitors. Exp Hematol 2007; 35 (07) 1109-1118
  • 10 Zuccolo E, Bottino C, Diofano F. , et al. Constitutive store-operated Ca(2+) entry leads to enhanced nitric oxide production and proliferation in infantile hemangioma-derived endothelial colony-forming cells. Stem Cells Dev 2016; 25 (04) 301-319
  • 11 Léauté-Labrèze C, Hoeger P, Mazereeuw-Hautier J. , et al. A randomized, controlled trial of oral propranolol in infantile hemangioma. N Engl J Med 2015; 372 (08) 735-746
  • 12 Phillips RJ, Penington AJ, Bekhor PS, Crock CM. Use of propranolol for treatment of infantile haemangiomas in an outpatient setting. J Paediatr Child Health 2012; 48 (10) 902-906
  • 13 Chang L, Gu Y, Yu Z. , et al. When to stop propranolol for infantile hemangioma. Sci Rep 2017; 7: 43292
  • 14 Ji Y, Chen S, Xu C, Li L, Xiang B. The use of propranolol in the treatment of infantile haemangiomas: an update on potential mechanisms of action. Br J Dermatol 2015; 172 (01) 24-32
  • 15 Zou HX, Jia J, Zhang WF, Sun ZJ, Zhao YF. Propranolol inhibits endothelial progenitor cell homing: a possible treatment mechanism of infantile hemangioma. Cardiovasc Pathol 2013; 22 (03) 203-210
  • 16 Strub GM, Kirsh AL, Whipple ME. , et al. Endothelial and circulating C19MC microRNAs are biomarkers of infantile hemangioma. JCI Insight 2016; 1 (14) e88856
  • 17 Li D, Li P, Guo Z, Wang H, Pan W. Downregulation of miR-382 by propranolol inhibits the progression of infantile hemangioma via the PTEN-mediated AKT/mTOR pathway. Int J Mol Med 2017; 39 (03) 757-763
  • 18 Moccia F, Zuccolo E, Poletto V. , et al. Endothelial progenitor cells support tumour growth and metastatisation: implications for the resistance to anti-angiogenic therapy. Tumour Biol 2015; 36 (09) 6603-6614
  • 19 Yang JZ, Ho AL, Ajonuma LC. , et al. Differential effects of Matrigel and its components on functional activity of CFTR and ENaC in mouse endometrial epithelial cells. Cell Biol Int 2003; 27 (07) 543-548
  • 20 Moccia F, Dragoni S, Lodola F. , et al. Store-dependent Ca(2+) entry in endothelial progenitor cells as a perspective tool to enhance cell-based therapy and adverse tumour vascularization. Curr Med Chem 2012; 19 (34) 5802-5818
  • 21 Borghesi A, Massa M, Campanelli R. , et al. Circulating endothelial progenitor cells in preterm infants with bronchopulmonary dysplasia. Am J Respir Crit Care Med 2009; 180 (06) 540-546
  • 22 Dominici M, Le Blanc K, Mueller I. , et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8 (04) 315-317
  • 23 Javed MJ, Mead LE, Prater D. , et al. Endothelial colony forming cells and mesenchymal stem cells are enriched at different gestational ages in human umbilical cord blood. Pediatr Res 2008; 64 (01) 68-73
  • 24 Moccia F, Guerra G. Ca(2+) signalling in endothelial progenitor cells: friend or foe?. J Cell Physiol 2016; 231 (02) 314-327
  • 25 Lodola F, Laforenza U, Bonetti E. , et al. Store-operated Ca2+ entry is remodelled and controls in vitro angiogenesis in endothelial progenitor cells isolated from tumoral patients. PLoS One 2012; 7 (09) e42541
  • 26 Rosti V, Massa M, Vannucchi AM. , et al; Italian Registry of Myelofibrosis with Myeloid Metaplasia; Myeloproliferative Disorders Research Consortium. The expression of CXCR4 is down-regulated on the CD34+ cells of patients with myelofibrosis with myeloid metaplasia. Blood Cells Mol Dis 2007; 38 (03) 280-286
  • 27 Oh BJ, Kim DK, Kim BJ. , et al. Differences in donor CXCR4 expression levels are correlated with functional capacity and therapeutic outcome of angiogenic treatment with endothelial colony forming cells. Biochem Biophys Res Commun 2010; 398 (04) 627-633
  • 28 Lamy S, Lachambre MP, Lord-Dufour S, Béliveau R. Propranolol suppresses angiogenesis in vitro: inhibition of proliferation, migration, and differentiation of endothelial cells. Vascul Pharmacol 2010; 53 (5-6): 200-208
  • 29 Annabi B, Lachambre MP, Plouffe K, Moumdjian R, Béliveau R. Propranolol adrenergic blockade inhibits human brain endothelial cells tubulogenesis and matrix metalloproteinase-9 secretion. Pharmacol Res 2009; 60 (05) 438-445
  • 30 Lodola F, Laforenza U, Cattaneo F. , et al. VEGF-induced intracellular Ca2+ oscillations are down-regulated and do not stimulate angiogenesis in breast cancer-derived endothelial colony forming cells. Oncotarget 2017; 8 (56) 95223-95246