VOLUME 11 NUMBER 1 • MARCH 2014
23
SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
Diabetes and stem cells: endogenous effects and
reparative mechanisms
Jason Seewoodhary, Peter J Evans
Abstract
Stem cells offer a novel approach to diabetes care based
on regeneration, which can potentially shift treatment
paradigms towards curation; therapeutic approaches have
honed in on generating functional stem cell-derived islet cells
for transplantation. Other approaches include stimulating
endogenous stem cell replication followed by differentiation
into functional islet cells
in situ
. This review critically considers
the impact of diabetes on endogenous stem cells and discusses
the potential utility of stem cell therapies for the treatment of
diabetes.
Keywords:
embryonic, pluripotent, stem cell, islet cell, diabetes,
transplantation, bone marrow
Introduction
The clinical utility of stem cells in diabetes care is based on
regeneration with the aim of repairing and replacing diseased
islet and vascular endothelial cells. Stem cell technology provides
a potentially limitless purified population of patient- and disease-
specific islet and endothelial cells, which confer a range of clinical
benefits that include understanding the pathogenesis of diabetes,
facilitating drug discovery for diabetes, and generating islet cells
for transplantation. This review will critically consider the effects of
diabetes on resident endogenous stem cells and the potential utility
of stem cells to treat diabetes.
Stem cells
Stem cells are undifferentiated cells capable of unlimited
proliferation and self-renewal while retaining the potential towards
differentiation into any cell type of endodermal, ectodermal
or mesodermal origin. There are three main types of stem cells:
embryonic (ES), adult, and induced pluripotent (iPS) stem cells.
ES cells are pluripotent cells derived from the inner cell mass of
the developing blastocyst.
1
ES cells confer the advantage of being
renewable, accessible to genetic modifications, expandable
in vitro
for lengthy periods. Thus ES cells can be yielded in high purified
quantities for potential regenerative purposes. Disadvantages of
ES cells include a relatively high tumorigenic potential, transplant
rejection, and ethical concerns relating to disaggregating the
developing blastocyst.
2
Correspondence to: Jason Seewoodhary
Department of Diabetes Mellitus and Endocrinology, Royal Gwent Hospital,
Cardiff Road, Newport, Gwent,
NP20 2UB, UK.
e-mail:
Previously published in:
Br J Diabetes Vasc Dis
2013;
13
(5–6); 224–228
S Afr J Diabetes Vasc Dis
2014;
11
: 23–26
Adult stem cells are multipotent cells. They are derived from
specific tissues within the embryo, foetus or adult, for example
the bone marrow, which contains two types of adult stem cells,
namely, mesenchymal and haematopoietic stem cells. Advantages
of adult stem cells include self-renewability, fewer ethical issues
relative to ES cells, and the potential to be harvested from
easily accessible organs and expanded. However, in contrast to
ES cells, adult stem cells are rarer in number in mature tissues.
This is significant as large numbers of cells are needed for stem
cell replacement therapies. Furthermore, adult stem cells have a
superior safety profile with a lower tumorigenic potential relative
to ES cells. However, this has recently been challenged by the
first report of a donor-derived brain tumour following neural
stem cell therapy.
3
Disadvantages include a lower degree of
plasticity, expandability and renewability, coupled with a greater
susceptibility to senescence compared with ES cells, and invasive
harvesting methods, for example bone marrow trephine and
biopsy to obtain mesenchymal stem cells (MSCs).
Induced pluripotent stem cells are derived from nonpluripotent
somaticcellssuchasdermalfibroblasts,whichhavebeentransformed
and genetically ‘reprogrammed’ into a pluripotent state akin to ES
cells. This is achieved by transfection with transcription factors such
as
Oct-3/4, Sox 2
and
Nanog
, which are core transcription factors
that repress the expression profile of differentiated cells and activate
an array of genes involved in pluripotency.
4
Other key transcription
factors include
Klf-4, Lin28
and
c-Myc
. Four traditional strategies
are available to reprogramme somatic cells to an iPS cell state: viral
transduction, nuclear transfer, cell fusion, and cell explantation.
Limitations of the transcription factor approach to generate iPS cells
include a low throughput, mutations being inserted into the target
cells genome, tumours, especially with
c-Myc
; and incomplete
reprogramming. These limitations can be overcome by novel
techniques to make iPS cells, which include ES cell-specific micro-
RNA (miRNA) to prompt iPS cell reprogramming,
5
biomimicry with
recombinant proteins injected into cells via polyarginine anchors,
which has coined the nomenclature ‘piPSCs’ – protein-induced
pluripotent stem cells,
6
and small compound mimicking, which
raises reprogramming efficiency.
7
iPS cells offer the advantage of being easily and non-invasively
harvested, useful tools for drug development, models of
disease processes
in vitro
, and an autologous source of cells for
transplantation with lower risks immunorejection. Disadvantages
include a propensity towards tumorigenesis and a lack of long-
term data on stability and safety.
8
The effects of diabetes on resident stem cells
The bone marrow is a primary target for diabetes-induced damage
of resident stem cells within the osteoblastic niche. This occurs
through two mechanisms, namely ‘diabetic stem cell mobilopathy’,
which refers to dysregulated control of osteoblastic stem cell
mobilisation into the peripheral circulation,
9
and diabetes-induced
bone marrow microangiopathy.
10
