Biomedical Engineering Reference
In-Depth Information
from recruitment to plasticity. This task, in turn, is complicated by the fact that we
do not yet understand the mechanisms underlying cell-based cardiac repair. For
instance, the efficacy of skeletal muscle myoblasts [
34
] provided the impetus for
human trials of skeletal muscle cells, but in the rabbit, diastolic functions are
improved even by injected fibroblasts [
35
] and systolic performance improved to
the same degree with bone marrow-derived cells as with skeletal muscle ones [
36
] .
Along with the issue of skeletal muscle cells' electrical isolation from host myocar-
dium, this prompts the question of how mechanical improvements arise even in this
ostensibly straightforward instance. Another reason to consider potential indirect
mechanisms is that studies have called into question the extent to which bone mar-
row-derived cells implanted in the heart form cardiomyocytes [
35-
37
] . The major-
ity of this review is, therefore, devoted to the biological horizons—namely
mobilization, homing, neoangiogenesis, and cardiac differentiation, and to evolving
new insights that may enable cell therapy for cardiac repair to surpass the present
state of the art.
Mechanisms of action
: Progenitor cells may improve functional recovery of infarcted
or failing myocardium by various potential mechanisms, including direct or indirect
improvement of neovascularization [
38-
43
]. Paracrine factors released by progeni-
tor cells may inhibit cardiac apoptosis, affect remodeling, or enhance endogenous
repair (e.g., by tissue-resident progenitor cells). Differentiation into cardiomyocytes
may contribute to cardiac regeneration. The extent to which these different mecha-
nisms are active may critically depend on the cell type and setting, such as acute or
chronic injury.
Hematopoietic or blood stem cells are critical to the daily production of over ten
billion blood cells and are the basis for bone marrow transplant therapy for cancer,
in the first instance. Rare and difficult to identify, these cells are extremely powerful
at regenerating blood and immune cells but only if they travel to the proper location
when introduced into the body. Typically the cells are infused into a vein, and they
find their way to the bone marrow through a process that depends on largely
unknown molecules. They are concentrated in bone marrow niche, the space close
to internal wall of the bone and surrounded by macrophages and fi bro, (Fig.
15.1
)
under very low oxygen tension compared to physiological.
The Molecules That Facilitate Homing of Stem Cells
into Damaged Tissue Areas
How the stem cells may mediate this improvement in damaged tissue is not well
understood. Ellis, Penn, and other investigators were, and still are considering addi-
tional mobilizing agents that may recruit a different subpopulation of stem cells,
and are beginning to unravel the signaling cascade that directs stem cells to
the infarct zone, as well as helps them transform or attract the other cells needed in
the regenerative process [
13
]. Penn has identified the gene that codes for one of the
