Keywords
Cardiovascular disease; Transplantation; Stem cell therapy; Immunobiology
Introduction
Scientists all over the world are racing to advance transplantation
therapies for wide-ranging medical diseases and disorders. Our laboratory
(Figure 1A) is focused on the development of new medical treatments
for cardiovascular disease, the leading cause of death worldwide. Many
of the current viable treatment options for cardiovascular disease
rely on transplanting genetic material that does not match that of the
donor recipient (i.e. allogeneic organs or tissues). Whether in response
to transplantation of full organs, tissues, or cells, the recipient body’s
propensity to reject transplanted material is one of the greatest hurdles
currently in the way of creating successful clinical treatments.
Our laboratory believes that to effectively treat the many sides
of cardiovascular disease, it is important to cultivate a myriad of
diverse clinical options. Our “wide angle lens” approach to disease
research includes developing methods for preventing post-treatment
complications, bioengineering tissue for transplantation, and promoting
effective stem cell therapies (Figure 1B). By pursing these and other
research directions in parallel, we hope to combat cardiovascular disease
from multiple angles. Here we describe several of our recent findings, and
discuss possible future research directions.
In 2014, we proposed that dichloroacetate could be used to prevent
in-stent restenosis [1]. In-stent restenosis is a potentially deadly posttreatment
complication, and is characterized by extreme amounts of
smooth muscle cell (SMC) proliferation. In an injury model of myointima
formation, SMCs displayed both a higher proliferation rate and resistance
to apoptosis. Interestingly, at the same time the membrane potential of
the SMC’s mitochondria became hyperpolarized. We identified pyruvate
dehydrogenase kinase 2 (PDK2) as a regulator of these phenomena. By
blocking PDK2 function pharmacologically (with dichloroacetate) or
genetically (through a lentiviral approach), the hyperpolarization of the
mitochondrial membrane potential was reduced and SMCs regained their
ability to enter apoptosis. Since dichloroacetate weakens the pathogenesis
associated with in-stent restenosis and has a narrow range of molecular
targets, it a strong candidate for future use in preventing post-treatment
development of proliferative vascular diseases.
Despite significant advances in clinical research, cardiovascular disease
remains the number one cause of death worldwide. Until recently, organ
transplantation has been the major technique for treating heart disease,
but this option faces severe difficulties since organ availability is low
and often accompanied by an excruciatingly long wait. The “holy grail”
of cardiovascular research would be development of an efficient method
to regenerate cardiac tissue in patients. One promisingly innovative
method to repair heart tissue relies on transplanting stem cells into
the myocardium. While stem cell therapy has shown great potential,
rejection of transplanted allogeneic stem cell material has constrained the
prospective positive effects of this technique. With this in mind, it has been
suggested that quick and easy generation of patient-specific pluripotent
stem cells could be accomplished by somatic cell nuclear transfer (SCNT).
While the creation of such cells can be successfully achieved, we have
recently shown that transplanting nuclear transfer-derived embryonic
stem cells (NT-ESCs) causes a strong adaptive immune response to due
to their allogeneic mitochondrial DNA [2]. Mismatched-mitochondrial
proteins appear to cause NT-ESCs to be readily rejected by the recipient.
Further research on stem cell therapies should take into account the effects
of non-autologous mitochondria on immune system rejection.
Bioengineering heart tissue is another potential method to restore nonfunctional
myocardial tissue after ischemic heart injury. However, how
the transplant recipient’s immune system will react to the scaffolding of
bioengineered tissue remains an open question. In our laboratory, we
tested a fibrin-based matrix as the structural basis for growing transplantready
heart tissue from autologous cells in an animal model [3]. After
transplantation, although the fibrin matrix itself caused an increased
immune response, it did not appear to affect the long-term retention of
the transplanted syngeneic cells. This suggests the future possibility of
using a fibrin-matrix scaffold to support patient-specific stem cell-derived
tissue grafts.
Laboratories worldwide, including our own, continue to pursue
numerous important open scientific questions with regard to transplant
immunology, including how to prevent post-transplant rejection of
allogeneic material. While patient-specific induced pluripotent stem cells
would be one solution to this problem, generation of individual patient
cell lines is extremely time, cost, and labor intensive. A more pragmatic
option would be to molecularly modify the immunogenicity of a stem cell
line in order to create a ready-for-use “off the shelf ” cell line. Alternatively,
generating a local hypo-immunogenic environment would be a novel
method to prevent post- transplant rejection of allogeneic material;
however, such a method has yet to be described. Successfully developing
either of these technologies would be highly beneficial to both researchers
and clinicians.
Figure 1: Worldwide, diverse treatment methods are being developed in the race to combat cardiovascular disease.
(A) Our laboratory takes a “wide angle lens” approach to disease research, pursuing a myriad of research directions in parallel.
(B) We discuss here three recent studies from our laboratory, including novel research directions for preventing post-treatment complications,
bioengineering tissue for transplantation, and generating stem cell therapies.
Over time, scientific research has moved toward specialization, with
most projects focusing only on one particular area of disease treatment.
We believe that specific research goals are of great importance, as they
provides strong and direct insight into problems, but we also believe that
diverse diseases – such as cardiovascular disease – require diverse and
individualized treatment options. Simultaneously approaching numerous
solutions using multiple progressive technologies is our best bet for
generating effective clinical therapeutics.
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Article Information
Article Type: Editorial
Citation: Miller KK, Schrepfer S (2015) Transplant
and Stem Cell Immunobiology: Translational
Directions for Cardiovascular Disease Research.
Transplant Res J 1(1): doi http://dx.doi.
org/10.16966/2473-1730.e101
Copyright: © 2015 Miller KK, et al. This is an
open-access article distributed under the terms
of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Publication history:
Received date: 23 Nov 2015
Accepted date: 24
Nov 2015
Published date: 30 Nov 2015