Biomedical Engineering Reference
In-Depth Information
Table 15.1 Inspiration and driving force for clinical studies: animal models
Donald Orlic (NIH, Bethesda, MD)
(mice) (2001) Nature
Hamano H (Japan) (2001) (sheep, rabbit model of
hindlimb ischemia, Lewis rats-autologous BM transplants)
A. Mouse [ 27 ]
B. Sheep
AMI→ same
AMI→ ligation of circumflex arterial branches
Mobilization (noninvasive)
BM biopsy (surgical, invasive method)
Lin− c-kit+ BMC from syngeneic
animals
SCF and G-CSF
29 BMC in normal to 7,200 in
cytokine-treated animals
3 × 10 4 -2 × 10 5 /5 mL PBS injected
2.5 mL PBS containing cells
4.22 × 10 8 cells/3 mL injected in ten sites across the
infarcted area through the reopened thoracotomy
Basic postulates: The best established source for adult stem cells is the BM. It contains different
cell types. HSCs posses plasticity and transdifferentiate into myocardial cells
Cell mobilization : Different aspects. The first hints that cytokine-induced mobiliza-
tion may be a way to enhance cardiac repair came as an extrapolation of findings of
results from efforts to increase EPC levels for neovascularization in another con-
text—hind limb ischemia. Indeed, VEGF [ 87 ] and GM-CSF [ 88 ] were found to
augment EPC levels and improve neovascularization, and subsequent studies docu-
mented EPC mobilization by numerous other proangiogenic growth factors—
stromal cell-derived factor-1 (SDF-1), angiopoietin-1, placental growth factor, and
erythropoietin [ 89- 91 ]. A wide array of interventions even more accessible clini-
cally than growth factor administration enhance the number of circulating EPCs in
adults, including treatment with HMG CoA reductase inhibitors (statins) and estro-
gens as well as exercise [ 92- 94 ]. The effect of EPC upon myocardial revasculariza-
tion is documented in dogs and might be applied in humans, as well. The CXR4
receptor-SDF-1 axis functions in homing HSCs and EPCs to the bone marrow
microenvironment, while by employing hemotactic isolation to SDF-1 gradient,
these cells can be mobilized.
Most studies confirmed an improvement in endothelial regeneration or neovas-
cularization by mobilizing agents. However, such functional improvements may
not rely entirely on EPC mobilization but may also—at least in part—be explained
by direct proangiogenic or antiapoptotic effects. Hence, as discussed as a recurring
theme in this review, the existence of known (and potential unknown) pleiotropic
modes of action complicates the interpretation of regenerative therapies, even in
cases where the beneficial effect is clear-cut and assured. A shift in emphasis from
the heart's vessels to the heart itself was prompted by the report that bone marrow-
derived cells can differentiate into cardiomyocytes when injected into injured
myocardium and regenerate the heart effectively [ 27 ]. Based on this discovery,
hematopoietic stem cell-mobilizing factors—G-CSF and SCF (Kit ligand)—were
used to improve cardiac regeneration experimentally (Orlic et al.), which quickly
led to the initiation of clinical trials studying the ability of G-CSF to mobilize
 
Search WWH ::




Custom Search