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450 Part V: Therapeutic Principles Chapter 30: Regenerative Medicine: Multipotential Cell Therapy for Tissue Repair 451

The regenerative potential of MSCs has long been sought as a tool to by Intracoronary Infusion of Selected Population of Stem Cells in Acute
rebuild and replace tissues damaged by acute or chronic injury whereby Myocardial Infarction (REGENT) study, which still only showed mod-
injected cultured MSCs activate endogenous repair mechanisms and est success. 62
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disappear in the process. In this capacity, MSCs in preclinical models The moderate success of marrow-derived MNCs spurred the
have been shown to alleviate ischemic injury in the heart, brain, and investigation of other populations of adult progenitor cells, as well as
kidneys; toxic insults to lung and liver; and degenerative damage to new routes of administration. The investigations led to the discovery
joints; and it is possible that in some settings allogeneic MSCs may be of MSCs, as well as endogenous cardiac-derived stem cells, that could
even more effective than autologous MSCs. 48 differentiate into cardiomyocytes and endothelial cells in animal mod-
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Lastly, MSCs are relatively easy to gene-modify and thus can be els. These findings led to clinical studies comparing marrow-derived
used as cellular vectors for delivering gene therapeutic agents in both MNCs versus the new MSCs used for intracoronary injection into
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inborn genetic disorders and acquired conditions, such as in antican- patients with ischemic cardiomyopathy. These tests showed signifi-
cer therapy or for trophic factor support after surgery. cant improvement in left ventricle ejection fraction in response to MSC
treatment.
To date, the clinical success of cell therapy approaches for cardiac
REGENERATIVE MEDICINE regeneration has been mixed. This is in contrast to the promising early
CARDIAC REPAIR preclinical studies that showed significant improvement in many differ-
ent measures of cardiac function. This difference has been attributed to
Cardiovascular disease is a leading cause of death in the world, leading the differences between rodent cardiac injury models and human clini-
to an estimated 17 million deaths per year. As life expectancy in the cal pathology, the cell population administration route, the origin of the
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developed world rises, so too do risk factors associated with chronic cell populations, and the limited number of cells injected.
heart disease. It is estimated that there are approximately 800,000 new ESCs, because of their pluripotency and unlimited ability to pro-
cases of acute myocardial infarction (AMI) annually. Heart failure liferate, have been the subject of extensive preclinical investigation for
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occurs when there is significant deprivation of oxygen to cardiac tissue, many tissues, particularly cardiac tissue repair. 65,66 However, there has
which results in decreased cardiac output and function as a result of loss been less enthusiasm for hESC-derived cardiomyocytes for human cell
of cardiomyocytes, scar formation, and tissue remodeling. Identifying therapy because their allogeneic nature requires concomitant immu-
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ways to regenerate or repair heart tissue will be key to developing effec- nosuppressive therapy and because ethical issues surround their deri-
tive treatment options for heart failure. vation. Despite these challenges, clinical studies have begun to collect
Since the mid-1990s, scientists have been investigating the poten- ESCs for cardiac differentiation with the intent of being used in a trial
tial of adult progenitor cells for use in heart regeneration. These early for AMI patients. However, as about any somatic cell can be used to
studies were triggered by the discovery that certain adult tissue-specific generate embryonic stem-like iPSCs, with the capability to differen-
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stem cells could be differentiated in vitro to become cardiac-like cells. tiate into cardiomyocytes, endothelial cells, and smooth muscle cells.
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This discovery led to many preclinical studies that assessed the ability Initial preclinical studies of murine iPSC-derived cardiomyocytes,
of adult stem cells to repair or enhance cardiac function after various injected into ischemic myocardium, led to rejection of transplanted
types of injury. cells by immune reaction as well as continuous proliferation that led
The cells reported to differentiate in vitro to cardiac-like cells in vivo to teratoma formation. Although iPSCs are attractive for their alloge-
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are satellite cells, which are undifferentiated skeletal muscle myoblasts, neic potential they have potential disadvantages for human cell therapy
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which led to studies using autologous skeletal myoblasts surgically based on their oncogenic nature, epigenetic memory, and maintenance
implanted into the heart muscle. Although these cells survived for short of potency for other cells types.
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periods of time, they retained their intrinsic contractile properties and Growing tissues in vitro for use in regenerative therapies has been
did not fully integrate into the cardiac tissue, which led to arrhythmias investigated as another delivery method of cells for heart repair. This
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and gave little long-term significant benefit in overall heart function. tissue engineering approach involves seeding cells onto scaffolds and
Some marrow-derived cell populations (lin−; c-kit+) were capable growing them for later engraftment or for the generation of whole
of differentiating to myocytes expressing cardiomyocyte markers such organs. In these systems, cells are transplanted with the scaffolding to
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as Nkx2.5, Gata4, and MEF. These marrow-derived cells were shown the cardiac wall, which provides structural support and a better micro-
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to survive in infarcted hearts and were capable of differentiating into environment for the migration of cells into the damaged myocardium. 71
smooth muscle and endothelial cells but not cardiomyocytes in vivo. A common theme in most preclinical and clinical cell therapy-based
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Additional studies demonstrated that other marrow-derived progenitor studies is the demonstration of improvements in cardiac function that is
cell populations (endothelial progenitors, angioblasts, or CD34+ cells) not correlated to number of cells injected or their longevity after admin-
were able to contribute to angiogenesis and neovascularization of the istration. This observation has led investigators to speculate that trans-
infarcted myocardium. This differed from more immature marrow planted cells improve cardiac function through paracrine rather than
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progenitor populations, called side-population cells (Lin− c-kit+ Sca- structural effects. This model suggests that observed improvements in
1+), that not only contribute to neovascularization but also regenerate myocardial regeneration or vasculogenesis are a result of transplanted
myocardium. These marrow-derived side-population cells homed to cells secreting molecules that are known to improve cardiovascular
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the border zone of infarction and resulted in improved left ventricu- function after injury. The effects of paracrine factors include decreased
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lar function. The cardiac regeneration capacity of the marrow-derived inflammation, increased angiogenesis, induction of proliferation of car-
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progenitor cells facilitated large-scale clinical studies using heteroge- diomyocytes or protection of existing ones, and activation of endoge-
neous populations of bone mononuclear cells (MNCs), also called epi- nous stem cells. Ischemic hearts subjected to secreted factors showed
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thelial progenitor cells (EPCs), for cardiac repair in patients with AMI 59,60 an increase in the expression of genes involved in cardiogenesis and a
or ischemic cardiomyopathy. These studies showed only moderate downregulation of cell-death markers, effects that contribute to survival
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improvements, and therefore led to further refinement of the selection of ischemic cardiomyocytes. The advantage of the paracrine model is
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criteria for marrow-derived cells (CD34+/CD133+) and changes in the the potential for the commercial development of paracrine factors that
route of administration (intracoronary injection) in the Regeneration have proven potential for cardiac repair.

Kaushansky_chapter 30_p0447-0458.indd 450 9/17/15 6:07 PM