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VOLUME 13 NUMBER 2 • DECEMBER 2016
REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
unpurified population containing stromal cells, endothelial
progenitor cells, fibroblasts and haematopoietic stem cells,89
which were used to produce neo-vascular cells. The multipotential
mesenchymal precursor cells that are harboured within the SVF
may not only be differentiated into adipocytes,
90-92
but also bone-
forming osteoblasts,
90,93,94
muscle myoblasts,
93,95
cardiomyocytes
96
and cartilage-forming chondrocytes.
90,93
Consequently, there
is considerable interest in these adipose-derived stromal cells
(ADSCs)
93,94
for regenerative medicine. This is not only for the
replacement of damaged fat,
97
bone,
98-100
muscle
101
and cartilage,
102
for it has been found that ADSCs also secrete cytokines, such as
VEGF, HGF and SDF-19,
103,104
which stimulate angiogenesis. These
cells may therefore be used to treat ischaemic disease,
105
such as
fibrosis and osteoradionecrosis, which are late complications of
radiotherapy.
106
It has also been found that the growth factors that
ADSCs secrete stimulate fibroblast and keratinocyte growth and
therefore ADSCs have been used to aid skin repair.
107
Unlike bone
marrow-derived stromal cells (BMSCs), a prominent redeeming
feature of ADSCs is their ease of isolation.
108
ADSCs and fat transplantation have been successfully used
after trauma and surgical resection such as mastectomy,
109,110
where ADSCs help to abrogate problems with angiogenesis and
the long-term viability of grafts.
111-113
ADSCs have also been used
to treat lipodystrophy,
114
which has become common due to side
effects of antiretroviral therapies (ART) in HIV-positive patients.
115,116
These ADSCs are expanded in number
in vitro
and differentiated
into mature adipocytes using a cocktail including insulin, the
cAMP inducer IBMX, a PPARg agonist indomethacin and a low
concentration of a glucocorticoid such as dexamethasone.
117,118
The
use of different cocktails enables ADSCs to be differentiated into
osteoblasts, myocytes or chondrocytes.
Lee
et al
.
119
was the first to demonstrate that ADSCs could be
differentiated into bone-forming osteoblasts and these cells were
used to heal critically sized calvarial defects in mice. In a direct
comparison during this investigation, ADSCs were found to have
the same efficacy as BMSCs. It was established, using genetic
analysis that 96% of the new bone was from the female donor
rather than from the male recipient.
120
As both adults and children
over the age of two years are unable to correct large cranial defects
due to inadequate ossification, this application has direct relevance
in man and was first used to correct a 120-cm
2
defect in a seven-
year-old girl with a severe head injury.
121
The differentiation of ADSCs into myocytes is relatively inefficient
and gives a low yield and low reproducibility.
89
Glucocorticoids
and 5% horse serum are used to supplement the growth media
to stimulate the fusion of cells to form multi-nucleated myotubes
which express myocyte markers.
90,93,122
Although
in vitro
differentiation is far from optimal, these cells
have been used to correct defects in the tibialis anterior muscle in a
mouse model for Duchennes’s muscular dystrophy.
The differentiation of ADSCs into chondrocytes is also
inefficient. Insulin, TGF
β
1 and ascorbic acid
122,123
are used to
stimulate chondogenesis in ADSCs, which takes two weeks, but
unfortunately the yield is far less than when using BMSCs.
123
As
cartilage repair in vivo is often difficult and slow, the use of ADSCs to
treat traumatised and arthritic joints and to aid joint reconstruction
still warrants further research
102
and promises to improve therapy
for cartilage repair in the future.
Adult mesenchymal stem cells isolated from the adipose tissue of
rabbits are able to differentiate into cardiomyocytes when treated
with 5-azacytidine.
96
This process has also been observed in human
ADSCs cultured in the presence of dimethylsulfoxide.
124
Furthermore,
such cells were used to improve cardiac function and increase
survival rate in a rodent model of myocardial infarction.
124
Similar
results were obtained in experiments in which undifferentiated
ADSCs were transplanted into rodent
125,126
and porcine
127
infarcted
hearts. These data suggest that at least in non-human models
of myocardial infarction, ADSCs may be used to repair damaged
cardiac tissue, although their utility in humans is still not known
and requires further investigation.
Fat and the future
The future certainly looks secure for fat. The prevalence of obesity
in the developing world shows no sign of abating, although recent
data from the USA shows evidence of plateauing.
128
The rising
levels of obesity in Africa were expected to result in an increase
in the prevalence of obesity-related disorders, which seems to be
the case.
71,129
Africa is also the centre of an HIV/AIDS epidemic and
is therefore suffering a double burden of communicable and non-
communicable diseases. Studies have shown that HIV infection and
ART can both lead to cardiovascular disease
130
and this will further
enhance the current epidemic of obesity-related diseases on the
African continent. Consequently, the use of ART has converted our
view of HIV infection from a certain death sentence to a chronic
disease, and this is leading to the development of health service
infrastructures that can be used for HIV diagnosis, ART roll out and
patient follow up. Such infrastructure could also be utilised for the
diagnosis and monitoring of non-communicable diseases in both
HIV-positive and HIV-negative subjects.
131
There are a number of interesting aspects of obesity in African
populations that deserve continued investigation. The more
diabetogenic than atherogenic nature of adiposity in African
comparedtoEuropeansubjectsisnotwellunderstoodandunravelling
the molecular mechanisms involved in such ethnic differences may
well uncover new aetiological pathways of obesity-related diseases.
The difference in body fat distribution between population groups
is also worthy of further study, particularly as African subjects have
less visceral fat than BMI-matched Europids, and yet are more
insulin resistant.
77-79
The use of high-throughput gene-screening
technology, which has yielded important information on the
polygenic nature of obesity via genome-wide association studies
132
should therefore be used in African populations to determine the
genetic input to adiposity and body fat distribution. It is possible
that ethnic differences in insulin sensitivity and the prevalence of
obesity-related disorders are due to differences in the secretory
output of adipocytes. The comparison of adipocyte secretomes
across population groups using the new technologies developed
for the analysis of complex mixtures of bioactive molecules
133
may
therefore be very worthwhile.
The future of the use of adipose-derived stromal cells (ADSCs)
for the treatment of human disease looks very promising. Such
cells have already been used to correct cranial defects in humans,
119
and preliminary studies in man to rectify cardiovascular
134,135
and
soft tissue
136-138
defects hold hope for the future use of ADSCs in
the treatment of muscle and cartilage defects and heart infarcts.
However, before this becomes a reality, there are a number of
technical problems that need to be overcome. The methods used
for the large-scale isolation of ADSCs and their efficient conversion
into the correct cell phenotype must be improved and standardised.