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Cardiovascular Regenerative Cell Therapy Heart
failure principally caused by ischemic heart disease is common and its
prevalence is increasing worldwide (1). Contrary to previous understandings,
myocardium continuously regenerates throughout life with an increased rate of
regeneration after large myocardial infarctions (2). This regeneration is,
however, limited to the viable myocardium and its border zone. Additionally,
there is a net loss of cardiomyocytes during myocardial infarction, resulting in
the remodeling and the impairment of cardiac-pump function (3,4). Early
reperfusion therapy results in myocardial salvage and significant reduction of
early mortality rates (5). However, post-infarction heart failure due to
ventricular remodeling remains a major problem (6). Enhancement of the
regeneration of cardiomyocytes has been shown to stimulate neovascularization of
the infracted area, reversing postinfarction heart failure (7-11). Bone
marrow harbors adult stem cells and progenitor cells with vast differentiation
potential including the capability for solid-organ repair (12,13). In animal
models of myocardial infarction, intramyocardial or intravenous injections of
bone marrow derived cells (BMC) have shown improved left ventricular function
angiogenesis, reduced apoptosis, and reduced remodeling (14,15). Human
clinical pilot studies have shown that intracoronary infusion of BMC is feasible
and beneficially affects postinfarction remodeling processes in Acute Myocardial
Infarction (AMI) patients (8-11, 18,19). Enhanced Autologous Bone Marrow Stem Cell Therapy (EBMSTM) To
improve beneficial effects of autologous BMCs as a source for cardiac
regenerative cell therapy we have used our biomaterial microarray hydrogel
microenvironment niche high throughput screening technology, Microplate
Biomaterial Microarray (MBMTM), to develop ideal hematopoietic
modeled microenvironment niche for ex-vivo maintenance of BMCs prior to
transplantation into patients. Our approach for screening and identification of
ideal conditions are shown in the schematics below. Animal testing of Enhanced
Bone Marrow Cells (EBMCTM) as a therapy in rat AMI model has been
completed. We are currently completing other preclinical studies and are in the
planning phases for human trials.
References 1)
2001 Heart and stroke statistical update. 2000.
Braunwald E. Cardiovascular medicine at
the turn of the millennium: triumphs, concerns,
and opportunities. N Engl J Med 1997;337:1360-9.
2)
Beltrami AP, Urbanek K, Kajstura J, et al.
Evidence that human cardiac myocytes divide
after myocardial infarction. N Engl J
Med 2001;344:1750-7. 3)
Pfeffer MA, Braunwald E. Ventricular remodeling
after myocardial infarction: experimental
observations and clinical implications. Circulation 1990;81:1161-72. 4)
Braunwald E, Bristow MR. Congestive heart
failure: fifty years of progress. Circulation 2000;102:Suppl 4:IV-14–IV-23. 5)
Lange RA, Hillis LD. Reperfusion therapy in acute myocardial infarction. N Engl
J Med 2002;346:954-5. 6)
Sutton MG, Sharpe N. Left ventricular remodeling
after myocardial infarction: pathophysiology
and therapy. Circulation 2000;101:2981-8. 7)
Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous
intracoronary mononuclear bone marrow
cell transplantation in humans. Circulation 2002;106:1913-8. 8)
Assmus B, Schachinger V, Teupe C, et al.
Transplantation of Progenitor Cells and Regeneration
Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation
2002;106:3009-17. 9)
Britten MB, Abolmaali ND, Assmus B,
et al. Infarct remodeling after intracoronary progenitor cell treatment in
patients with acute myocardial infarction (TOPCARE-AMI):
mechanistic insights from serial
contrast-enhanced magnetic resonance
imaging. Circulation 2003;108: 2212-8. 10)
Wollert KC, Meyer GP, Lotz J, et al. Intracoronary autologous bone-marrow cell
transfer after myocardial infarction: the
BOOST randomised controlled clinical
trial. Lancet 2004;364:141-8. 11)
Schachinger V, Assmus B, 12)
Korbling M, Estrov Z. Adult stem cells for
tissue repair — a new therapeutic concept? N Engl J Med 2003;349:570-82. 13)
Ratajczak MZ, Kucia M, Reca R, Majka M, Janowska-Wieczorek A, Ratajczak J. Stem
cell plasticity revisited: CXCR4-positive cells expressing mRNA for early
muscle, liver and neural cells ‘hide out’ in the bone marrow. Leukemia
2004;18:29–40. 14)
Fuchs S, Baffour R, Zhou YF, et al. Transendocardial
delivery of autologous bone marrow
enhances collateral perfusion and regional function in pigs with
chronic experimental myocardial ischemia.
J Am Coll Cardiol 2001;37:1726-32. 15)
Kocher AA, Schuster MD, Szabolcs MJ, et
al. Neovascularization of ischemic myocardium by human bone-marrow-derived
angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and
improves cardiac function. Nat Med
2001;7:430-6. 16)
17)
Orlic D, Kajstura J, Chimenti S, et al. Bone
marrow cells regenerate infarcted myocardium.
Nature 2001;410:701-5. 18)
Dimmeler S, Aicher A, Vasa M, et al. HMG-CoA
reductase inhibitors (statins) increase
endothelial progenitor cells via the
PI 3-kinase/Akt pathway. J Clin Invest 2001;108:391-7. 19)
Vasa M, Fichtlscherer S, Adler K, et al. Increase
in circulating endothelial progenitor cells by statin therapy in patients
with stable coronary artery disease. Circulation 2001;103:2885-90. |
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