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the discovery that mature adult differentiated somatic cells can be reprogrammed to a pluripotent state
to create an unlimited source of any cell in the body. The ability to generate human induced PSC-derived
cardiomyocytes (PSC-CMs) from adult cells has further broadened interest and study in the use of these
cells in the heart. A number of investigators are now culturing these cells, developing methods to maintain
[3-6]
differentiated cell phenotype, and studying healthy and diseased human cardiomyocytes . Much of this
work looks at reprogramming somatic cells from healthy and diseased donors to study known mutations
and deficiencies of cardiomyocytes, as well as identify potential treatments. Hurdles regarding target
identification and drug development have been attributed to variability in phenotype, thus the growing
[7,8]
body of work in this area .

Prior to the development of PSCs, the early work with cell-based therapy for acute myocardial infarction
and chronic heart failure (CHF) involved administering varying adult somatic cell populations. With the
[9]
exception of the skeletal myoblasts , these approaches proved safe but had limited therapeutic efficacy with
respect to improved cardiac function and structural remodeling [10,11] . With the advent of PSCs it became
possible for investigators to create the functional building blocks of the heart allowing for the development
of tissue engineering (TE) approaches, cellular reprogramming, and gene editing to optimize the delivery
of tissue function specific cells to the damaged heart [12-23] .

AUTOLOGOUS VS. ALLOGENEIC PREPARATIONS
Early in the evolution of cell-based therapies there was enthusiasm to use autologous approaches with
the patient’s own cells so as to avoid immune rejection. However, it has become clear that limitations
with autologous approaches exist: sample collection and preparation from individual patients is time-
consuming, costly and may ultimately lack efficacy because of problems with cellular genome stability
and regenerative potential. To overcome these limitations, allogeneic approaches have been adopted using
screened, optimal donors. This donor vetting improves both the quality and potency of the cell product,
increases cell availability, and decreases cost through scaled manufacturing. The paradigm switch from
autologous to allogeneic was observed with the first clinical trial using PSC derived cells for age-related
macular degeneration, which started with autologous preparations but subsequently changed to using
[24]
allogeneic cells .

IMMUNE CONSIDERATIONS
Immunologic rejection is something relevant for all proposed cell-based therapies . The concept
[25]
of accounting for the immune system is based on the belief that PSC derived cells are not immune-
privileged because of Human Leukocyte Antigen (HLA)/ABO antigens. Investigators have suggested that
the expression of these antigens in PSC-derived cells equates them with any other organ transplants,
all of which require immune suppression . Immunosuppressive agents such as cyclosporine and
[26]
tacrolimus have been used for solid organ transplant and described extensively in pre-clinical studies of
TE preparations. However, they are costly, may be cytotoxic, and cause adverse effects. There is a clinical
trial in Japan using PSC-CMs in patients with CHF patients where the patients receive non-HLA mapped
allogeneic cardiomyocytes and are given immune suppression . The use of HLA mapping is one option
[27]
by which to circumvent immunosuppressive agents; allogeneic cell lines of HLA-typed donors could be
generated to maximally match each recipient, though an identical match is statistically improbable. Such
a strategy would require creating and maintaining large cell banks. Generating personalized products for
individual patients from the bank would be expensive and require HLA typing of every patient. The ability
to edit candidate therapeutic cell lines is also being explored, to make a hypo-immune cell, one that would
be considered “universal”. Each cell line could be edited to remove HLAs while still maintaining markers
of identity so as to go undetected as foreign by the immune system, theoretically eliminating the need for