Scope of tissue engineering - Biomedical Engineering Desk Reference - page 713

7.2.8.3 Cell therapy

Given the complexity of organ-specific microenvi-
ronmental cues essential for functional incorporation of
transplanted EPCs and CEPs, numerous hurdles have to
be overcome for successful stem cell therapy for tissue
vascularization. As damaged tissue may lose anatomical
cues for functional organ neovascularization, in vitro
manipulation of stem cells may be essential to facilitate
in vivo incorporation. Identification of organ-specific
cytokinesdincluding the appropriate combinations of
VEGFs, FGFs, PDGFs, IGFs, angiopoietins, other as-
yet-unrecognized factors and ECM components for op-
timal culture conditionsdwill provide the platform for
the differentiation of stem cells, allowing delivery of
a large number of angiocompetent cells.

Stem cell therapy is an emerging field, but current clin-
ical experience is limited. One limitation of cell therapy
is that donor cells often cannot functionally replace the
impaired cells immediately following transplantation and
this delay may impact patient survival. In the field of
adult stem cell therapy, it is estimated that there are
currently over 80 therapies and around 300 clinical trials
underway using such cells [34] . Hematopoietic stem cell
transplants are routine clinical practice and more than
300 patients with type I diabetes have now undergone
transplants of islet cells using the so-called ''Edmonton
protocol'', with a significant proportion staying off insulin
injections for several years. But the field remains beset by
problems of reproducibility. Often, the level of thera-
peutic benefit is minimal as implanted cells die because
of immune attack or other problems. It is commonly not
clear whether cells are expanding, fusing with recipient
cells, or exerting an effect through secreted growth fac-
tors. Unraveling these problems will require progress on
several fronts.

7.2.8.3.2 Cardiac malfunction
Myocardial infarctions most commonly result from cor-
onary occlusions, due to a thrombus overlying an ath-
erosclerotic plaque. Because of its high metabolic rate,
myocardium (cardiac muscle) begins to undergo irre-
versible injury within 20 minutes of ischemia, and
a wavefront of cell death subsequently sweeps from the
inner layers toward the outer layers of myocardium over
a 3- to 6-h period. Although cardiomyocytes are the most
vulnerable population, ischemia also kills vascular cells,
fibroblasts, and nerves in the tissue. Myocardial necrosis
elicits a vigorous inflammatory response. Hundreds of
millions of marrow-derived leukocytes, initially com-
posed of neutrophils and later of macrophages, enter the
infarct. The macrophages phagocytose the necrotic cell
debris and likely direct subsequent phases of wound
healing. Concomitant with removal of the dead tissue,
a hydrophilic provisional wound repair tissue rich in
proliferating fibroblasts and endothelial cellsdtermed
''granulation tissue''dinvades the infarct zone from the
surrounding tissue. Over time, granulation tissue re-
models to form a densely collagenous scar tissue. In most
human infarcts, this repair process requires 2 months to
complete. At the organ level, myocardial infarction re-
sults in thinning of the injured wall and dilation of the
ventricular cavity. These structural changes markedly
increase mechanical stress on the ventricular wall and
promote progressive contractile dysfunction. The extent
of heart failure after a myocardial infarction is directly
related to the amount of myocardium lost.
Related to myocardial repair following injury, the
limited proliferative capacity of mature cardiomyocytes
is the fundamental reason that numerous investigators
have evaluated alternative cell sources. Cellular cardio-
myoplasty to replace damaged myocardial cells has been
attempted using a variety of cell types including bone-
marrow precursor cells, skeletal myoblasts, satellite cells,
muscle-derived stem cells, smooth muscle cells, late
embryonic/fetal and neonatal cardiac cells, and ES cells.
Umbilical cord blood cells have the capacity to form

7.2.8.3.1 Angiogenesis
Adult bone marrow is a rich reservoir of tissue-specific
stem and progenitor cells. Among them is a scarce
population of cells known as ''endothelial progenitor
cells'' (EPCs) that can be mobilized to the circulation and
contribute to the neoangiogenic processes. Circulating
endothelial progenitor cells (CEPs) have been detected in
the circulation either after vascular injury or during tumor
growth. The CEPs primarily originate from EPCs within
the bone marrow and differ from sloughed mature, cir-
culating endothelial cells (CECs) that randomly enter the
circulation as a result of blunt vascular injury. Preclinical
studies have shown that introduction of bone marrow-
derived endothelial and hematopoietic progenitors can
restore tissue vascularization after ischemic events in
limbs, retina, and myocardium [33] . Co-recruitment of
angiocompetent hematopoietic cells delivering specific
angiogenic factors facilitates incorporation of EPCs into
newly sprouting blood vessels. Given the morbidity asso-
ciated with limb ischemia, vascular stem cell therapy
provides promising adjunct therapy to current bypass
surgical approaches. In preclinical studies, introduction of
bone marrow-derived EPCs effectively improves collat-
eral vessel formation, thereby minimizing limb ischemia.
In patients suffering from peripheral arterial disease,
placement of autologous whole bone-marrow MNCs into
ischemic gastrocnemius muscle resulted in restoration of
limb function. Because MNCs contain both EPCs and
myeloid cells, it remains to be determined whether the
improvement in these studies was due in part to the in-
troduction of myelomonocytic cells.