Our goal is to build vascular networks from human endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs) to re-build damaged tissues and organs. We and others have shown that human EPCs and SMPCs can be obtained from blood or bone marrow and expanded in the laboratory without difficulty. Our published and preliminary data demonstrate the vasculogenic capability of these cells in vivo using a Matrigel model and immunodeficient mice. In the future, we envision use of a patient's own EPCs and SMPCs for a variety of tissue-engineering (TE) applications and for in situ regeneration of vascular networks in ischemic tissue. For tissue- engineering (TE), vascular networks created from EPCs/SMPCs would be incorporated into tissue- engineered constructs in vitro such that upon implantation in vivo, anastomoses with the host circulation occur rapidly to establish blood flow. For tissue regeneration in situ, EPCs/SMPCs would be delivered to the site in vivo where they will undergo vasculogenesis, as we have demonstrated can occur in an in vivo Matrigel model. Our overall hypothesis is that EPCs and SMPCs applied to either a tissue-engineered (TE) organ or in situ to ischemic tissue will establish an adequate blood supply and thereby promote resident cells to undergo appropriate tissue development and regeneration. In this proposal, we will determine key parameters to accelerate the vasculogenic process to a time frame of 24-48 hours using the in vivo model we have established with human EPCs and SMPCs. Next, we will test the ability of vascular networks preformed in vitro within biodegradable scaffolds to form anastomoses with the host circulation upon implantation in vivo. Finally, we will test whether EPC/SMPCs will undergo vasculogenesis in ischemic myocardium and if so, evaluate the effect on recovery of the heart. In summary, we envision our two-cell system as an enabling technology that can be applied to many different tissues/organs wherein functional blood vessels are needed. We also view cell-based regenerative approaches as a continuum - from TE in which autologous cells seeded onto scaffold materials are stimuated by biochemical and mechanical forces to form tissue, to in situ tissue regeneration in which endogenous cellular repair processes are enhanced by a number of different mechanisms. Along this continuum, the timing and degree of vascularization will be a critical component for rebuilding complex tissues. Public Health Relevance Statement (provided by applicant): Our goal is to determine if vascular networks created from blood- or bone marrow-derived endothelial and smooth muscle progenitor cells will alleviate ischemia and promote tissue repair. In essence we are testing whether jump-starting the vascularization process with two highly purified and defined cell types will augment and/or accelerate the endogenous repair and regenerative mechanisms. We propose that this two-cell system is an enabling technology that can be applied to many different tissues and organs wherein functional blood vessels are needed. This proposal will focus on repair of ischemic myocardium, but we envision that our strategy for tissue vascularization will be applicable to tissue-engineering and to many aspects of regenerative medicine.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094262-04
Application #
8130783
Study Section
Special Emphasis Panel (ZEB1-OSR-D (M1))
Program Officer
Lundberg, Martha
Project Start
2008-09-26
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2011
Total Cost
$576,132
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Kang, Kyu-Tae; Lin, Ruei-Zeng; Kuppermann, David et al. (2017) Endothelial colony forming cells and mesenchymal progenitor cells form blood vessels and increase blood flow in ischemic muscle. Sci Rep 7:770
Allen, Patrick; Kang, Kyu-Tae; Bischoff, Joyce (2015) Rapid onset of perfused blood vessels after implantation of ECFCs and MPCs in collagen, PuraMatrix and fibrin provisional matrices. J Tissue Eng Regen Med 9:632-6
Sawada, Naoki; Jiang, Aihua; Takizawa, Fumihiko et al. (2014) Endothelial PGC-1? mediates vascular dysfunction in diabetes. Cell Metab 19:246-58
Kang, Kyu-Tae; Coggins, Matthew; Xiao, Chunyang et al. (2013) Human vasculogenic cells form functional blood vessels and mitigate adverse remodeling after ischemia reperfusion injury in rats. Angiogenesis 16:773-84
Kang, Kyu-Tae; Allen, Patrick; Bischoff, Joyce (2011) Bioengineered human vascular networks transplanted into secondary mice reconnect with the host vasculature and re-establish perfusion. Blood 118:6718-21
Allen, Patrick; Melero-Martin, Juan; Bischoff, Joyce (2011) Type I collagen, fibrin and PuraMatrix matrices provide permissive environments for human endothelial and mesenchymal progenitor cells to form neovascular networks. J Tissue Eng Regen Med 5:e74-86
Melero-Martin, Juan M; De Obaldia, Maria E; Kang, Soo-Young et al. (2008) Engineering robust and functional vascular networks in vivo with human adult and cord blood-derived progenitor cells. Circ Res 103:194-202