DF/HCC Program Affiliation

Angiogenesis, Invasion, and Metastasis

Research Abstract

The goal of my laboratory is to develop cell-based technologies that will allow engineering vascularized tissues in vivo using postnatal progenitor cells obtained from patients by non-invasive means. In particular, our focus is on the combined use of bone marrow-derived mesenchymal progenitor cells (MPCs) and human blood-derived endothelial progenitor cells (EPCs) to regenerate adipose and skeletal muscle tissues in vivo lost after tumor resections (e.g., mastectomy and carcinoma removal). The research conducted in my laboratory is trying to address whether generating a vascular implants with highly purified and defined MPCs and EPCs will drive tissue development in vivo. We hypothesize that for this to happen, 1) both MPCs and EPCs need first to create a vascular network that will allow blood perfusion through the implants; and 2) this vascularization will promote resident cells to undergo appropriate tissue development by adopting the phenotype of the surrounding tissue at the site of implantation. We have previously characterized the phenotype of human MPCs and EPCs and demonstrated the ability of these cells to form vascular networks in vivo within 7 days after implantation. In addition, our preliminary data also show that the formation of vascular networks is accompanied by a progressive appearance of differentiated cells throughout the implants and that these differentiated cells are specific to the site of implantation (i.e., adipocytes in subcutaneous implants and myocytes in intramuscular implants). We propose that this two-cell, two-step system is a cell-based technology that can be applied to many different tissues/organs wherein functional blood vessels are needed. We are currently focused on formation of adipose tissue and skeletal muscle, but we envision that our strategy will be applicable to many aspects of regenerative medicine. What is unique about our approach, in comparison to most tissue engineering approaches, is that 1) the tissues are developed entirely in vivo (i.e., using the body’s regenerative capacity), and 2) we incorporate highly defined EPCs as one of the cellular building blocks. We give priority to the initial establishment of a functional vascular network within the implant, and propose that as a result of this neo-vascularization appropriate tissue formation and remodeling will be achieved.

Publications

• Melero-Martin JM,Santhalingam S,Al-Rubeai M.Methodology for optimal in vitro cell expansion in tissue engineering.Adv Biochem Eng Biotechnol 2009;112:209-29.
  19290503
• Melero-Martin JM,Bischoff J.Chapter 13. An in vivo experimental model for postnatal vasculogenesis.Methods Enzymol 2008;445:303-29.
  19022065
• 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 Jul 18;103(2):194-202.
  18556575
• 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 Jul;118(7):2592-9.
  18535669
• 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 Jun 1;109(11):4761-8.
  17327403
• 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 growt
  16973908
• 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 Aug 1;108(3):915-21.
  16861344
• Melero-Martin JM,Dowling MA,Smith M,Al-Rubeai M.Expansion of chondroprogenitor cells on macroporous microcarriers as an alternative to conventional monolayer systems.Biomaterials 2006 May;27(15):2970-9.
  16455134
• Melero-Martin JM,Dowling MA,Smith M,Al-Rubeai M.Optimal in-vitro expansion of chondroprogenitor cells in monolayer culture.Biotechnol Bioeng 2006 Feb 20;93(3):519-33.
  16259002