Photo of Joyce E. Bischoff,  PhD

Joyce E. Bischoff, PhD

Boston Children's Hospital

Boston Children's Hospital
Phone: (617) 919-2192
Fax: (617) 730-0231


joyce.bischoff@childrens.harvard.edu

Joyce E. Bischoff, PhD

Boston Children's Hospital

EDUCATIONAL TITLES

  • Professor, Surgery, Harvard Medical School
  • Research Associate, Surgery, Boston Children's Hospital
  • Principal Investigator, Surgery and Vascular Biology Program, Boston Children's Hospital

Research Abstract

Hemangioma is a tumor of endothelial cells that occurs in infants. These tumors can grow rapidly, causing organ damage and disfigurement and even threatening life. However, a fascinating aspect is that hemangiomas regress over the course of several years, beginning at one year of age. In my laboratory, we are elucidating the cellular and molecular mechanisms that drive this uncontrolled growth and the spontaneous regression. Recently, we identified endothelial progenitor cells in proliferating hemangiomas the first demonstration of these cells in a human vascular tumor.

We are also working on how normal endothelial progenitors in blood might be used for cardiovascular repair and tissue-engineering. In a sheep model, we showed that autologous endothelial progenitor cells can be isolated from 15-20 milliliters of peripheral blood and used to create small diameter blood vessels. We also envision the use of blood-derived endothelial progenitors to repair or replace cardiac valves. To pursue this, we are studying growth and differentiation pathways in normal cardiac valve endothelium. Two of our studies have shown that valve endothelial cells from adult tissue can recapitulate processes that occur during valve development. These pathways involve TGF-β and VEGF signaling. We hypothesize that endothelial progenitors, expanded ex vivo, can be induced to behave as valve endothelial cells and thereby manipulated, via tissue engineering processes, to create viable long-lived tissue valve substitutes.

Publications

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  • Boscolo E, Coma S, Luks VL, Greene AK, Klagsbrun M, Warman ML, Bischoff J. AKT hyper-phosphorylation associated with PI3K mutations in lymphatic endothelial cells from a patient with lymphatic malformation. Angiogenesis 2015; 18:151-62. PubMed
  • Jia D, Huang L, Bischoff J, Moses MA. The endogenous zinc finger transcription factor, ZNF24, modulates the angiogenic potential of human microvascular endothelial cells. FASEB J. 2015; 29:1371-82. PubMed
  • Shapero K, Wylie-Sears J, Levine RA, Mayer JE, Bischoff J. Reciprocal interactions between mitral valve endothelial and interstitial cells reduce endothelial-to-mesenchymal transition and myofibroblastic activation. J Mol Cell Cardiol 2015; 80:175-85. PubMed
  • Wylie-Sears J, Levine RA, Bischoff J. Losartan inhibits endothelial-to-mesenchymal transformation in mitral valve endothelial cells by blocking transforming growth factor-็กซ-induced phosphorylation of ERK. Biochem Biophys Res Commun 2014; 446:870-5. PubMed
  • Smadja DM, Guerin CL, Boscolo E, Bieche I, Mulliken JB, Bischoff J. ็•™6-Integrin is required for the adhesion and vasculogenic potential of hemangioma stem cells. Stem Cells 2014; 32:684-93. PubMed
  • Allen P, Kang KT, Bischoff J. Rapid onset of perfused blood vessels after implantation of ECFCs and MPCs in collagen, PuraMatrix and fibrin provisional matrices. 2013. PubMed
  • Kang KT, Coggins M, Xiao C, Rosenzweig A, Bischoff J. Human vasculogenic cells form functional blood vessels and mitigate adverse remodeling after ischemia reperfusion injury in rats. Angiogenesis 2013. PubMed
  • Boscolo E, Mulliken JB, Bischoff J. Pericytes from infantile hemangioma display proangiogenic properties and dysregulated angiopoietin-1. Arterioscler Thromb Vasc Biol 2013; 33:501-9. PubMed
  • Smadja DM, Mulliken JB, Bischoff J. E-selectin mediates stem cell adhesion and formation of blood vessels in a murine model of infantile hemangioma. Am J Pathol 2012; 181:2239-47. PubMed
  • Stiles J, Amaya C, Pham R, Rowntree RK, Lacaze M, Mulne A, Bischoff J, Kokta V, Boucheron LE, Mitchell DC, Bryan BA. Propranolol treatment of infantile hemangioma endothelial cells: A molecular analysis. Exp Ther Med 2012; 4:594-604. PubMed
  • Kang KT, Allen P, Bischoff J. Bioengineered human vascular networks transplanted into secondary mice reconnect with the host vasculature and re-establish perfusion. Blood 2011; 118:6718-21. PubMed
  • Boscolo E, Stewart CL, Greenberger S, Wu JK, Durham JT, Herman IM, Mulliken JB, Kitajewski J, Bischoff J. JAGGED1 Signaling Regulates Hemangioma Stem Cell-to-Pericyte/Vascular Smooth Muscle Cell Differentiation. Arterioscler Thromb Vasc Biol 2011; 31:2181-92. PubMed
  • Greenberger S, Yuan S, Walsh LA, Boscolo E, Kang KT, Matthews B, Mulliken JB, Bischoff J. Rapamycin Suppresses Self-Renewal and Vasculogenic Potential of Stem Cells Isolated from Infantile Hemangioma. J Invest Dermatol 2011. PubMed
  • Boscolo E, Mulliken JB, Bischoff J. VEGFR-1 Mediates Endothelial Differentiation and Formation of Blood Vessels in a Murine Model of Infantile Hemangioma. Am J Pathol 2011. PubMed
  • Greenberger S, Bischoff J. Infantile Hemangioma-Mechanism(s) of Drug Action on a Vascular Tumor. Cold Spring Harb Perspect Med 2012; 1:a006460. PubMed
  • Bischoff J, Aikawa E. Progenitor Cells Confer Plasticity to Cardiac Valve Endothelium. J Cardiovasc Transl Res 2011. PubMed
  • Allen P, Melero-Martin J, Bischoff J. Type I collagen, fibrin and PuraMatrix matrices provide permissive environments for human endothelial and mesenchymal progenitor cells to form neovascular networks. 2011; 5:e74-86. PubMed
  • Wylie-Sears J, Aikawa E, Levine RA, Yang JH, Bischoff J. Mitral valve endothelial cells with osteogenic differentiation potential. Arterioscler Thromb Vasc Biol 2011; 31:598-607. PubMed
  • Allen P, Melero-Martin J, Bischoff J. Type I collagen, fibrin and PuraMatrix matrices provide permissive environments for human endothelial and mesenchymal progenitor cells to form neovascular networks. 2011. PubMed
  • Greenberger S, Adini I, Boscolo E, Mulliken JB, Bischoff J. Targeting NF-่™œB in infantile hemangioma-derived stem cells reduces VEGF-A expression. Angiogenesis 2010; 13:327-35. PubMed
  • Melero-Martin J, De Obaldia ME, Allen P, Dudley AC, Klagsbrun M, Bischoff J. Host myeloid cells are necessary for creating bio-engineered human vascular networks in vivo. Tissue Eng Part A 2010; 16:2457-66. PubMed
  • Hjortnaes J, Gottlieb D, Figueiredo JL, Melero-Martin J, Kohler RH, Bischoff J, Weissleder R, Mayer J, Aikawa E. Intravital Molecular Imaging of Small-Diameter Tissue-Engineered Vascular Grafts: A Feasibility Study. 2010; 16:597-607. PubMed
  • Greenberger S, Boscolo E, Adini I, Mulliken JB, Bischoff J. Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells. N Engl J Med 2010; 362:1005-13. PubMed
  • Wu JK, Adepoju O, De Silva D, Baribault K, Boscolo E, Bischoff J, Kitajewski J. A switch in Notch gene expression parallels stem cell to endothelial transition in infantile hemangioma. Angiogenesis 2010; 13:15-23. PubMed
  • Jang GH, Park IS, Yang JH, Bischoff J, Lee YM. Differential functions of genes regulated by VEGF-NFATc1 signaling pathway in the migration of pulmonary valve endothelial cells. FEBS Lett 2009; 584:141-6. PubMed
  • Elmasri H, Karaaslan C, Teper Y, Ghelfi E, Weng M, Ince TA, Kozakewich H, Bischoff J, Cataltepe S. Fatty acid binding protein 4 is a target of VEGF and a regulator of cell proliferation in endothelial cells. FASEB J 2009; 23:3865-73. PubMed
  • Dal-Bianco JP, Aikawa E, Bischoff J, Guerrero JL, Handschumacher MD, Sullivan S, Johnson B, Titus JS, Iwamoto Y, Wylie-Sears J, Levine RA, Carpentier A. Active adaptation of the tethered mitral valve: insights into a compensatory mechanism for functional mitral regurgitation. Circulation 2009; 120:334-42. PubMed
  • Ignatov A, Hoffman O, Smith B, Fahlke J, Peters B, Bischoff J, Costa SD. An 11-year retrospective study of totally implanted central venous access ports: Complications and patient satisfaction. Eur J Surg Oncol 2009; 35:241-6. PubMed
  • Boscolo E, Bischoff J. Vasculogenesis in infantile hemangioma. Angiogenesis 2009; 12:197-207. PubMed
  • Yang JH, Wylie-Sears J, Bischoff J. Opposing actions of Notch1 and VEGF in post-natal cardiac valve endothelial cells. Biochem Biophys Res Commun 2008; 374:512-6. PubMed
  • Dudley AC,Khan ZA,Shih SC,Kang SY,Zwaans BM,Bischoff J,Klagsbrun M. Calcification of multipotent prostate tumor endothelium. Cancer Cell 2008; 14:201-11. PubMed
  • Melero-Martin JM,De Obaldia ME,Kang SY,Khan ZA,Yuan L,Oettgen P,Bischoff J. Engineering robust and functional vascular networks in vivo with human adult and cord blood-derived progenitor cells. Circ Res 2008; 103:194-202. PubMed
  • Khan ZA,Boscolo E,Picard A,Psutka S,Melero-Martin JM,Bartch TC,Mulliken JB,Bischoff J. Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice. J Clin Invest 2008; 118:2592-9. PubMed
  • Picard A, Boscolo E, Khan ZA, Bartch TC, Mulliken JB, Vazquez MP, Bischoff J. IGF-2 and FLT-1/VEGF-R1 mRNA levels reveal distinctions and similarities between congenital and common infantile hemangioma. Pediatr Res 2008; 63:263-7. PubMed
  • Bischoff J, Griffioen AW. In memoriam Dr. Judah Folkman. Angiogenesis 2008; 11:1-2. PubMed
  • Malumbres M, Pevarello P, Barbacid M, Bischoff JR. CDK inhibitors in cancer therapy: what is next? Trends Pharmacol Sci 2007; 29:16-21. PubMed
  • Mulliken JB, Bischoff J, Kozakewich HP. Multifocal rapidly involuting congenital hemangioma: a link to chorangioma. Am J Med Genet A 2007; 143:3038-46. PubMed
  • Wu X, Lensch MW, Wylie-Sears J, Daley GQ, Bischoff J. Hemogenic endothelial progenitor cells isolated from human umbilical cord blood. Stem Cells 2007; 25:2770-6. PubMed
  • Melero-Martin JM, Khan ZA, Picard A, Wu X, Paruchuri S, Bischoff J. In vivo vasculogenic potential of human blood-derived endothelial progenitor cells. Blood 2007; 109:4761-8. PubMed
  • Paruchuri S, Yang JH, Aikawa E, Melero-Martin JM, Khan ZA, Loukogeorgakis S, Schoen FJ, Bischoff J. Human pulmonary valve progenitor cells exhibit endothelial/mesenchymal plasticity in response to vascular endothelial growth factor-A and transforming growth factor-beta2. Circ Res 2006; 99:861-9. PubMed
  • Khan ZA, Melero-Martin JM, Wu X, Paruchuri S, Boscolo E, Mulliken JB, Bischoff J. Endothelial progenitor cells from infantile hemangioma and umbilical cord blood display unique cellular responses to endostatin. Blood 2006; 108:915-21. PubMed
  • Yu Y, Fuhr J, Boye E, Gyorffy S, Soker S, Atala A, Mulliken JB, Bischoff J. Mesenchymal stem cells and adipogenesis in hemangioma involution. Stem Cells 2006; 24:1605-12. PubMed
  • Lee YM, Cope JJ, Ackermann GE, Goishi K, Armstrong EJ, Paw BH, Bischoff J. Vascular endothelial growth factor receptor signaling is required for cardiac valve formation in zebrafish. Dev Dyn 2005; 235:29-37. PubMed
  • Frieden IJ, Haggstrom AN, Drolet BA, Mancini AJ, Friedlander SF, Boon L, Chamlin SL, Baselga E, Garzon MC, Nopper AJ, Siegel DH, Mathes EW, Goddard DS, Bischoff J, North PE, Esterly NB. Infantile hemangiomas: current knowledge, future directions. Proceedings of a research workshop on infantile hemangiomas, April 7-9, 2005, Bethesda, Maryland, USA. Pediatr Dermatol 2005; 22:383-406. PubMed
  • Armstrong EJ, Bischoff J. Heart valve development: endothelial cell signaling and differentiation. Circ Res 2004; 95:459-70. PubMed
  • Wu X, Rabkin-Aikawa E, Guleserian KJ, Perry TE, Masuda Y, Sutherland FW, Schoen FJ, Mayer JE, Bischoff J. Tissue-engineered microvessels on three-dimensional biodegradable scaffolds using human endothelial progenitor cells. Am J Physiol Heart Circ Physiol 2004; 287:H480-7. PubMed
  • Yu Y, Moulton KS, Khan MK, Vineberg S, Boye E, Davis VM, O'Donnell PE, Bischoff J, Milstone DS. E-selectin is required for the antiangiogenic activity of endostatin. Proc Natl Acad Sci U S A 2004; 101:8005-10. PubMed
  • Yu Y, Flint AF, Mulliken JB, Wu JK, Bischoff J. Endothelial progenitor cells in infantile hemangioma. Blood 2003; 103:1373-5. PubMed
  • Li Q, Yu Y, Bischoff J, Mulliken JB, Olsen BR. Differential expression of CD146 in tissues and endothelial cells derived from infantile haemangioma and normal human skin. J Pathol 2003; 201:296-302. PubMed
  • Dvorin EL, Jacobson J, Roth SJ, Bischoff J. Human pulmonary valve endothelial cells express functional adhesion molecules for leukocytes. J Heart Valve Dis 2003; 12:617-24. PubMed
  • Dvorin EL, Wylie-Sears J, Kaushal S, Martin DP, Bischoff J. Quantitative evaluation of endothelial progenitors and cardiac valve endothelial cells: proliferation and differentiation on poly-glycolic acid/poly-4-hydroxybutyrate scaffold in response to vascular endothelial growth factor and transforming growth facto Tissue Eng 2003; 9:487-93. PubMed
  • Perry TE, Kaushal S, Sutherland FW, Guleserian KJ, Bischoff J, Sacks M, Mayer JE. Thoracic Surgery Directors Association Award. Bone marrow as a cell source for tissue engineering heart valves. Ann Thorac Surg 2003; 75:761-7; discussion 767. PubMed
  • Johnson EN, Lee YM, Sander TL, Rabkin E, Schoen FJ, Kaushal S, Bischoff J. NFATc1 mediates vascular endothelial growth factor-induced proliferation of human pulmonary valve endothelial cells. J Biol Chem 2002; 278:1686-92. PubMed
  • Bischoff J. Monoclonal expansion of endothelial cells in hemangioma: an intrinsic defect with extrinsic consequences? Trends Cardiovasc Med 2002; 12:220-4. PubMed
  • Yu Y, Flint A, Dvorin EL, Bischoff J. AC133-2, a novel isoform of human AC133 stem cell antigen. J Biol Chem 2002; 277:20711-6. PubMed
  • Yu Y, Varughese J, Brown LF, Mulliken JB, Bischoff J. Increased Tie2 expression, enhanced response to angiopoietin-1, and dysregulated angiopoietin-2 expression in hemangioma-derived endothelial cells. Am J Pathol 2001; 159:2271-80. PubMed
  • Paranya G, Vineberg S, Dvorin E, Kaushal S, Roth SJ, Rabkin E, Schoen FJ, Bischoff J. Aortic valve endothelial cells undergo transforming growth factor-beta-mediated and non-transforming growth factor-beta-mediated transdifferentiation in vitro. Am J Pathol 2001; 159:1335-43. PubMed
  • Kaushal S, Amiel GE, Guleserian KJ, Shapira OM, Perry T, Sutherland FW, Rabkin E, Moran AM, Schoen FJ, Atala A, Soker S, Bischoff J, Mayer JE. Functional small-diameter neovessels created using endothelial progenitor cells expanded ex vivo. Nat Med 2001; 7:1035-40. PubMed
  • 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; 107:745-52. PubMed
  • Luo J, Kato M, Wang H, Bernfield M, Bischoff J. Heparan sulfate and chondroitin sulfate proteoglycans inhibit E-selectin binding to endothelial cells. J Cell Biochem 2001; 80:522-31. PubMed
  • Tomlinson J, Wang JL, Barsky SH, Lee MC, Bischoff J, Nguyen M. Human colon cancer cells express multiple glycoprotein ligands for E-selectin. Int J Oncol 2000; 16:347-53. PubMed
  • Yu Y, Wylie-Sears J, Boscolo E, Mulliken JB, Bischoff J. Genomic Imprinting of IGF2 is Maintained in Infantile Hemangioma despite its High Level of Expression. Mol Med 2006; 10:117-23. PubMed
  • Smith LE, Shen W, Perruzzi C, Soker S, Kinose F, Xu X, Robinson G, Driver S, Bischoff J, Zhang B, Schaeffer JM, Senger DR. Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nat Med 1999; 5:1390-5. PubMed
  • Luo J, Paranya G, Bischoff J. Noninflammatory expression of E-selectin is regulated by cell growth. Blood 1999; 93:3785-91. PubMed
  • Luo J, Lin J, Paranya G, Bischoff J. Angiostatin upregulates E-selectin in proliferating endothelial cells. Biochem Biophys Res Commun 1998; 245:906-11. PubMed
  • Kr. A simplified method for growth of human microvascular endothelial cells results in decreased senescence and continued responsiveness to cytokines and growth factors. In Vitro Cell Dev Biol Anim 1998; 34:308-15. PubMed
  • Razon MJ, Kr. Increased apoptosis coincides with onset of involution in infantile hemangioma. Microcirculation 1998; 5:189-95. PubMed
  • Bischoff J. Cell adhesion and angiogenesis. J Clin Invest 1997; 100:S37-9. PubMed
  • Nguyen M, Corless CL, Kr. Vascular expression of E-selectin is increased in estrogen-receptor-negative breast cancer: a role for tumor-cell-secreted interleukin-1 alpha. Am J Pathol 1997; 150:1307-14. PubMed
  • Z. Hypoxia enhances stimulus-dependent induction of E-selectin on aortic endothelial cells. Proc Natl Acad Sci U S A 1996; 93:7075-80. PubMed
  • Kr. E-selectin is present in proliferating endothelial cells in human hemangiomas. Am J Pathol 1996; 148:1181-91. PubMed
  • Bischoff J, Brasel C. Regulation of P-selectin by tumor necrosis factor-alpha. Biochem Biophys Res Commun 1995; 210:174-80. PubMed
  • Nguyen M, Strubel NA, Bischoff J. A role for sialyl Lewis-X/A glycoconjugates in capillary morphogenesis. Nature 1993; 365:267-9. PubMed
  • Strubel NA, Nguyen M, Kansas GS, Tedder TF, Bischoff J. Isolation and characterization of a bovine cDNA encoding a functional homolog of human P-selectin. Biochem Biophys Res Commun 1993; 192:338-44. PubMed
  • Nguyen M, Folkman J, Bischoff J. 1-Deoxymannojirimycin inhibits capillary tube formation in vitro. Analysis of N-linked oligosaccharides in bovine capillary endothelial cells. J Biol Chem 1992; 267:26157-65. PubMed
  • Bischoff J, Moremen K, Lodish HF. Isolation, characterization, and expression of cDNA encoding a rat liver endoplasmic reticulum alpha-mannosidase. J Biol Chem 1990; 265:17110-7. PubMed
  • Bischoff J, Libresco S, Shia MA, Lodish HF. The H1 and H2 polypeptides associate to form the asialoglycoprotein receptor in human hepatoma cells. J Cell Biol 1988; 106:1067-74. PubMed
  • Bischoff J, Lodish HF. Two asialoglycoprotein receptor polypeptides in human hepatoma cells. J Biol Chem 1987; 262:11825-32. PubMed
  • Bischoff J, Kornfeld R. The soluble form of rat liver alpha-mannosidase is immunologically related to the endoplasmic reticulum membrane alpha-mannosidase. J Biol Chem 1986; 261:4758-65. PubMed
  • Bischoff J, Kornfeld R. The effect of 1-deoxymannojirimycin on rat liver alpha-mannosidases. Biochem Biophys Res Commun 1984; 125:324-31. PubMed
  • Bischoff J, Kornfeld R. Evidence for an alpha-mannosidase in endoplasmic reticulum of rat liver. J Biol Chem 1983; 258:7907-10. PubMed
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