Cardiovascular Research (2017) 113, 1064–1073 SPOTLIGHT REVIEW

doi:10.1093/cvr/cvx096

Adipose tissue depots and inflammation: effects

on plasticity and resident mesenchymal stem
cell function
Lina Badimon1,2* and Judit Cubedo1
1
Cardiovascular Science Institute – ICCC, IIB-Sant Pau, CiberCV, Hospital de Sant Pau, c/Sant Antoni MaClaret 167, Barcelona 08025, Spain; and
2
Cardiovascular Research Chair UAB, Barcelona, Spain

Received 30 January 2017; revised 4 April 2017; editorial decision 10 April 2017; accepted 10 May 2017; online publish-ahead-of-print 11 May 2017

Abstract Adipose tissue (AT) is a highly heterogeneous organ. Beside the heterogeneity associated to different tissue types
(white, brown, and ‘brite’) and its location-related heterogeneity (subcutaneous, visceral, epicardial, and perivascu-
lar, etc.), AT composition, structure, and functionality are highly dependent on individual-associated factors. As
such, the pro-inflammatory state associated to the presence of obesity and other cardiovascular risk factors
(CVRFs) directly affects AT metabolism. Furthermore, the adipose-derived stem cells (ASCs) that reside in the
stromal vascular fraction of AT, besides being responsible for most of the plasticity attributed to AT, is an additional
source of heterogeneity. Thus, ASCs directly contribute to AT homeostasis, cell renewal, and spontaneous repair.
These ASCs share many properties with the bone-marrow mesenchymal stem cells (i.e. potential to differentiate
towards multiple tissue lineages, and angiogenic, antiapoptotic, and immunomodulatory properties). Moreover,
ASCs show clear advantages in terms of accessibility and quantity of available sample, their easy in vitro expansion,
and the possibility of having an autologous source. All these properties point out towards a potential use of ASCs
in regenerative medicine. However, the presence of obesity and other CVRFs induces a pro-inflammatory state
that directly impacts ASCs proliferation and differentiation capacities affecting their regenerative abilities. The focus
of this review is to summarize how inflammation affects the different AT depots and the mechanisms by which
these changes further enhance the obesity-associated metabolic disturbances. Furthermore, we highlight the impact
of obesity-induced inflammation on ASCs properties and how those effects impair their plasticity.
䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏

Keywords Adipose tissue depots • Adipose-derived stem cells • Plasticity • Inflammation

䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏

This article is part of the Spotlight Issue on Dysfunctional Adipocyte and Cardiovascular Disease.

..
1. Introduction ..
..
deleterious or beneficial depending on how it affects AT functionality.
Moreover, the cellular and structural differences of the different fat
..
The adipose tissue (AT) is a highly heterogeneous organ due not only to .. depots also influence AT plasticity and remodelling. In fact, important dif-
the existence of different AT types, i.e. white AT (WAT), brown AT .. ferences exist between the two main WAT depots, visceral AT (VAT),
..
(BAT), and ‘brite’ (brown-in-white), but also because of its multi-depot .. that has been traditionally considered to have a protective role against
distribution. Moreover, both WAT and BAT coexist at several loca- .. trauma, and subcutaneous AT (SAT), usually considered an energy stor-
..
tions.1 Indeed, because of their high heterogeneity these AT depots have .. age organ. Both tissues have different structure (i.e. vascular density and
been even considered as ‘mini-organs’ with autonomous characteristics .. innervation), different adipokine expression profiles and thus, different
..
and functionality.2 .. metabolic functions.4,5 Importantly, VAT shows a higher acute inflamma-
Besides its heterogeneity, another key property of AT is its ability to .. tory profile than SAT, being therefore considered a more deleterious
..
change its structural, cellular and molecular characteristics depending on .. WAT depot.6
both physiological and pathological conditions that directly impact its .. Therefore, AT represents an extremely dynamic organ that can
..
functionality, a term that is known as plasticity.3 This plasticity can be .. exhibit important differences in its characteristics depending on

* Corresponding author. Cardiovascular Science Institute – ICCC, c/Sant Antoni MaClaret 167, 08025 Barcelona, Spain. Tel: þ34 935565880; fax: þ34 935565559, E-mail: lbadimon@csic-iccc.org
Published on behalf of the European Society of Cardiology. All rights reserved. V
C The Author 2017. For permissions, please email: journals.permissions@oup.com.
Inflammation, adipose tissue depots, and stem cells
..
conditioning/regulatory factors. One of the most evident and common ..
physiological changes observed in AT is the progressive reduction in ..
..
brown adipocytes with the concomitant increase in white adipocytes ..
observed with age.7,8 Interestingly, the inverse effect seems to be ..
..
observed after cold exposure both in rodents9 and in humans,10 repre- ..
senting a clear example of the potential beneficial plasticity of AT. ..
..
Similarly, physical activity can also promote browning of AT.11 ..
AT plasticity is also observed in many pathological situations such as in ..
..
the presence of cardiovascular risk factors (CVRFs), obesity being one of ..
the most determining factors inducing a metabolic shift in adipocytes ..
..
that leads to dysfunctional AT. Specifically, obese individuals show BAT ..
atrophy in association with increased fat accumulation in VAT and ..
..
hyperglycaemia.12 ..
Better understanding of the effects of the individual-related factors,
..
..
such as gender or age, and the clustering of CVRFs, such as hypercholes- ..
terolemia, hyperglycemia, and obesity-associated subclinical inflamma-
..
..
tion, on AT heterogeneity and plasticity is critical to design targeted ..
strategies to combat the presence of dysfunctional AT.
..
..
..
..
..
2. Obesity-induced inflammation ..
..
and AT depots
Human and animal model studies have shown that obesity is accompa-
nied by a significant increase in macrophage infiltration, and this recruit-
ment is linked to systemic inflammation, insulin resistance, and oxidative
stress.13 AT and inflammation are closely interrelated, not only because
of the chronic low-grade inflammation present in obesity,14 but also due
to the intrinsic ability of adipocytes to secrete both, anti- and pro-
inflammatory adipokines,15 their imbalance being determinant for AT
functional profile and the development of metabolic disorders.
Adipocytes of obese individuals are larger (hypertrophic adipocytes)
than those from lean subjects and change their adipokine secretion pro-
file towards a pro-inflammatory state producing lower levels of adipo-
nectin, but higher levels of tumour necrosis factor-alpha (TNF-alpha),
thus contributing to the pro-inflammatory milieu associated to obesity.16
This obesity-induced inflammation directly impacts AT functionality.17,18
In addition to adipocyte hypertrophy, excessive calorie consumption
promotes adipocyte hyperplasia, partly due to the differentiation of stem
cells towards adipocytes, process known as adipogenesis.19 On one
hand, newly formed adipocytes have increased sensitive to insulin and an
increased uptake of free fatty acids and triglycerides.20 On the other
hand, hypertrophied adipocytes become dysfunctional, loosing their abil-
ity to protect against systemic lipotoxicity, and leading to ectopic fat ac-
cumulation. Obesity is also characterized by the remodelling of the
extracellular matrix in order to allow tissue expansion.21 Additionally,
AT from obese subjects shows a decreased ability to expand the capil-
lary network that surrounds adipocytes leading to adipocyte hypoxia
and necrosis.22 As a result, obese AT is characterized by the presence of
crown-like structures (CLS) that are formed by infiltrating macrophages
surrounding necrotic adipocytes.23 However, how obesity and its associ-
ated inflammatory status affect AT plasticity is different depending on
the background characteristics of each AT depot.
2.1 Differential effects on VAT and SAT
Although overall fat mass has been linked to the development of
obesity-associated comorbidities, the accumulation of VAT has shown
1065
to be specifically associated to the development of metabolic complica-
tions.24,25 However, not all the VAT depots exhibit the same behaviour
in relation to obesity-associated inflammation and metabolic disturb-
ances. A recent study comparing three different VAT depots, mesen-
teric, omental, and periaortic, from patients with cardiovascular disease
(CVD), has described important differences in their inflammatory pro-
file.26 Specifically, periaortic VAT showed the highest adipokine secre-
tion ability although its morphological characteristics were not
associated to metabolic complications in obesity. On the contrary, au-
thors found that mesenteric AT, although showing a low inflammatory
profile depicted morphological features that were consistently associ-
ated to metabolic syndrome, with a higher adipocyte size and an
increased presence of CLS. Indeed, an important association between
the specific mesenteric depot and obesity has been reported.27 This
strong association has been explained by the anatomical location of this
fat depot, close to the intestine, in which the adipokines secreted by
mesenteric AT could directly influence the secretion of intestinal hor-
mones such as glucagon-like peptide-1 (GLP-1).28,29
Traditionally, a protective role against cardiometabolic disease has
been attributed to SAT.30 SAT depots show an enhanced adipocyte
generation capacity compared with VAT that might represent a pro-
.. tective property against metabolic dysfunction.31 However, obesity
.. does not only affect VAT depots, but it also disrupts SAT homeostasis.
..
.. Indeed, obesity also induces adipocyte hypertrophy and decreased
.. adipogenesis and angiogenesis in SAT.32 However, it has been re-
..
.. ported that obesity-mediated adipocyte hypertrophy is more frequent
.. in VAT, whereas adipocyte hyperplasia is more commonly found in
..
.. SAT.33 This difference is partly explained by the increased propensity
... to cell death observed in VAT and the higher amount of progenitor
.. cells observed in SAT.3 Nevertheless, CLS have also been found in
..
.. subcutaneous fat depots.34 However, it should be noted that func-
.. tional and morphological differences among superficial and deep SAT
..
.. depots have been reported.35
.. Several studies have tried to address the effects of obesity on VAT
..
.. and SAT and the differential contribution of both fat depots to the devel-
.. opment of chronic inflammation.36,37 The specific analysis of macrophage
..
.. infiltration has shown a higher infiltration rate in VAT than in SAT in
.. both, obese and normal-weight individuals.38 Regarding inflammatory
..
.. cytokines, it has been recently shown that whereas IL-6 and IL-15 levels
.. were higher in SAT than in VAT depots form obese and normal-weight
..
.. subjects, obesity was associated with an important shift towards a higher
.. pro-inflammatory profile of VAT with a significant increase in IL-6 and IL-
..
.. 15 in obese subjects compared with non-obese individuals. These results
..
.. highlight that obesity is associated with a shift towards a pro-
.. inflammatory state specifically in VAT. Furthermore, there was an addi-
..
.. tive effect of the presence of metabolic syndrome in obese patients that
.. showed significantly higher levels of IL-1b, IL-6, and IL-15 in VAT com-
..
.. pared with obese subjects without metabolic syndrome.39 Indeed, in vitro
.. experiments have shown that VAT-derived adipocytes secrete more
..
.. pro-inflammatory cytokines than SAT-derived adipocytes.15 Importantly,
... a correlation between IL-6 serum levels and the concentration of this
.. cytokine in SAT has been reported, supporting the obesity-mediated in-
..
.. crease of fat accumulation in this depot.39 In addition, by using a novel
.. labelling proteomic approach to analyse the secretome of VAT and SAT
..
.. depots from obese individuals, a specific increased secretion of extracel-
.. lular matrix proteins has been detected specifically in SAT.40 These re-
..
. sults underscore a stronger effect of obesity on extracellular matrix
1066 L. Badimon and J. Cubedo

..
over-production in SAT depots that could lead to fibrosis having a nega- .. secretion of pro-inflammatory cytokines, what has been named ‘outside-
tive influence on AT expansion by impairing adipogenesis. .. to-inside cellular cross-talk’.62,63 Obesity induces an increase in epicardial
..
.. AT thickness that has been associated with atrial enlargement and dia-
.. stolic function impairment.64 Furthermore, the enlargement of this AT
2.2. Effects on perivascular AT (PVAT) ..
PVAT represents a key AT depot in the context of CVD due to its intim-
.. depot has been related to metabolic syndrome through its effects on ar-
.. terial blood pressure, insulin, and LDL-cholesterol levels, among
ate contact with arterial beds. Indeed, PVAT is known to exert vasodila- ..
.. others.65 These effects have been related to the deleterious effects of
tory and anti-inflammatory functions that are blunted in obesity, where ..
.. toxic lipid intermediates through the activation of the inflammasome and
the volume of this depot increases proportionally to the increase in
.. the induction of mitochondrial dysfunction and apoptosis.66
VAT.41–43 Thus, PVAT expansion has also been described during obes- ..
.. Changes in epicardial AT have also been reported in patients with es-
ity.44 Rodent models under high-fat diet have white and brown peri-
.. tablished coronary artery disease (CAD). As such, PET studies have
aortic adipocytes hypertrophy.45 Importantly, local PVAT expansion has ..
.. shown that epicardial AT volume is a better independent predictor of
been associated to atherosclerotic plaque development and vascular cal-
.. myocardial ischaemia than coronary artery calcium score.67 This is con-
cifications.46 This association is mediated, at least in part, by the paracrine ..
.. sistent with the fact that patients with unstable angina show higher epi-
action of PVAT-derived growth factors that can stimulate vascular
.. cardial AT thickness than patients with stable angina. Furthermore, CAD
smooth muscle cell (VSMC) proliferation.47 Among these factors, visfatin ..
.. patients have a higher ratio of pro-inflammatory to anti-inflammatory
has been shown to induce VSMC growth via ERK 1/2 and p38.48 Indeed,
.. macrophages in epicardial AT than subjects without CAD,68 contributing
obesity is associated with increased circulating visfatin levels.49 ..
.. to this pro-inflammatory scenario in those patients. Indeed, a transcrip-
Decreased adiponectin PVAT secretion in obesity could have an add- .. tomic study on human epicardial AT has demonstrated a co-ordinated
itional role as this adipokine exerts an anti-proliferative action on .. change in the expression of several genes involved in key cellular func-
VSMC.50 Other PVAT-derived factors that could contribute to the obes- ..
.. tions in CAD patients compared with subjects without CAD.69
ity associated increase in atherosclerosis development are TNF-a, ..
.. All these evidence support the notion that epicardial AT changes dir-
VEGF, and leptin which have also been implicated in VSMC proliferation .. ectly affect cardiac function and thus CVD development.
and migration.51,52 Inflammation seems associated to adventitial vasa ..
vasorum expansion that by increasing the communication with PVAT
..
..
propagates the pro-inflammatory signals,53 having a pivotal role in vascu- .. 3. Adipose-derived stem cells
lar disease development. Thus, because of its location, PVAT is an essen-
..
..
tial player in the ‘outside-in’ theory supporting that vascular .. (ASCs)
inflammation begins in the adventitia and advances to the media and the
..
.. AT is composed mainly of two different cell categories: adipocytes, which
intima.54,55 Early obesity induced by high-fat diet in mice has shown to re- ..
duce the expression of adipogenesis-related genes in thoracic PVAT,
.. are the main parenchymal cell type; and the stromal vascular fraction
.. (SVF) containing the remaining cellular components. This SVF includes
and to induce a decrease in adiponectin and an increase in macrophage ..
.. preadipocytes, fibroblasts, endothelial cells, immune cells and multipotent
inflammatory protein 1-alpha (MIP-1a).56 Importantly, while these ..
.. stem cells.70 Adipocytes are the main cellular component of AT in terms
changes were seen in PVAT, minimal changes were detected in SAT and
.. of volume as they occupy more than 90% of the tissue due to their unique
VAT depots. Furthermore, high-fat diet also induces an imbalance in .. morphology containing a single large lipid droplet. However, the SVF is
anti-oxidant mechanisms in PVAT leading to oxidative stress that ampli- ..
.. the main cellular fraction in terms of quantity in the AT of both lean and
fies inflammation in this specific fat depot.57,58 Moreover, obesity induces ..
.. obese subjects. In 2013, the International Fat Applied Technology Society
a shift in PVAT from an anti-inflammatory profile towards a pro-
.. reached a consensus on the minimal phenotypic criteria to characterize
inflammatory status that is mainly orchestrated by MCP-1.59 In addition, ..
.. the adherent stromal/stem cell population from AT. Thus, it is now
experimental studies have demonstrated that PVAT from obese mice
.. accepted that ASCs are characterized as CD39þ/CD44þ/CD73þ/
have an impaired insulin-mediated vasodilation when compared with .. CD90þ/CD105þ/CD45-/CD31- cells.71 However, the expression of
non-obese animals, and that this effect was reversed by the inhibition of ..
.. ASCs surface markers, such as CD34, may change with division, and thus
inflammation through the blockade of the c-Jun N-terminal kinase (JNK) ..
.. different ASC subpopulations may exist in vivo, further contributing to AT
signalling pathway.60 .. heterogeneity.
Because of the intimate contact between PVAT and the vascular bed, ..
inflammation-mediated changes in PVAT can accelerate and propagate .. ASCs, contributing to tissue homeostasis, cell renewal and spontan-
.. eous repair, exert a physiological role in AT (Figure 1). These ASCs share
inflammation, oxidative stress and vascular dysfunction contributing to ..
vascular disease progression in the context of obesity.
.. many properties with bone-marrow mesenchymal stem cells such as
.. their potential to differentiate towards multiple tissue lineages, their abil-
..
.. ity to secrete angiogenic and antiapoptotic cytokines, and their immuno-
2.3 Effects on epicardial AT .. modulatory properties. Specifically, ASCs are able to differentiate into
..
Epicardial AT is the specific VAT depot of the heart that is found be- .. cardiomyocytes, muscle myoblasts, osteoblasts, chondrocytes, hepato-
tween the myocardial tissue and the visceral pericardium surrounding .. cytes, pancreatic cells, endothelial cells, and haematopoietic-supporting
..
both ventricles.61 Because of its anatomical location, and together with .. cells, among others,72–78 making them an excellent target in the research
PVAT, epicardial AT arises as one of the most important fat depots in re- .. field of regenerative medicine. Importantly, in vitro and in vivo animal stud-
..
lation to CVDs. Indeed, epicardial AT and the myocardium share the .. ies have revealed that ASC-conditioned media confers functional im-
same microcirculation having thus a clear functional relationship.62 .. provement and attenuation of injury in a similar way to that afforded by
..
The presence of established CVD or CVRFs has a direct impact on .. ASCs,79,80 suggesting that ASCs-effects could be mediated via complex
the epicardial fat depot. Moreover, changes in the phenotype of this spe-
.. paracrine actions. Indeed, ASCs have the capacity to secrete several
..
cific fat depot can directly impact heart function through the paracrine . growth factors and cytokines (i.e. transforming growth factor b1 (TGF-
Inflammation, adipose tissue depots, and stem cells
Figure 1 ASCs functionality in AT. ASCs influence AT homeostasis through their ability to: differentiate towards different lineages, express different
growth factors receptors and secrete cytokines and different mediators. In addition, ASCs are responsible, at least in part, of AT depot-related
heterogeneity.
..
b1), vascular endothelial growth factor, insulin-like growth factor, or ..
hepatocyte growth factor, among others), explaining some of the ..
..
observed effects of ASCs stimulating the recovery of damaged tissues.81 ..
In addition, ASCs are also targets of different growth factors as they have ..
..
been shown to express different growth factor receptors that are partly ..
responsible for their plasticity. One of the most relevant examples of the ..
..
plasticity of ASCs is their ability to secrete angiogenic factors under hyp- ..
oxic conditions, enabling them to survive in an ischaemic environment ..
..
..
where they provide a reservoir of the necessary growth factors to pro-
mote angiogenesis.82
..
..
The exact localization of ASCs within the AT has not been totally ..
identified, but there are evidence suggesting a perivascular location.
..
..
Importantly, ASCs also contribute to AT heterogeneity. Indeed, ASCs ..
from different depots show a different ability to grow and differentiate
..
..
(i.e. WAT vs. BAT) and even ASCs from different anatomical areas also ..
..
exhibit different characteristics. As such, ASCs derived from SAT and ..
VAT when differentiated in vivo, show important differences inherent to ..
..
the source tissue.83,84 The adipogenic differentiation capacity of SAT-
derived ASCs is higher than the one of ASCs from the VAT.85 This lim-
ited capacity of VAT ASCs to differentiate into new adipocytes could
partly explain the hypertrophy of existing adipocytes as a response to fat
accumulation in obesity. As opposed to this, the greater differentiation
capacity of SAT ASCs induces the formation of new adipocytes with
smaller lipid vacuoles.86 These existing differences between ASCs from
different fat depots appear to be the result of both, epigenetic regulation
in the early developmental phases and the specific environmental influ-
ence of each AT depot, representing a key factor contributing to the dif-
ferences in AT plasticity of different depots. Furthermore, specific
individual physiological and pathological conditions could induce add-
itional changes on ASCs even leading to the loss of their properties
1067
limiting their stemness and their regenerative potential.87–91 These indi-
vidual conditioning factors (age, CVRFs, etc.) affect ASCs properties and
represent a potential limitation for their autologous use in the clinical
setting for reparative purposes.92
4. Inflammation-induced changes
on ASCs
Importantly, it has been described that several individual-related factors
such as age or gender can modify the number and the proliferation, dif-
ferentiation, and angiogenic capacity of ASCs.93 Specifically, ageing has
been associated with a loss of the ASC growth and differentiation poten-
tial. Thus, younger ages (25–30 years) show a high differentiation rate in
all AT depots, whereas in older individuals the differentiation rate is only
high in the arm and thigh SAT depots.94 This loss of ASC differentiation
potential can be partly driven by the pro-inflammatory profile that char-
.. acterizes ageing.95 In fact, inflammation is believed to play a key role in
.. governing ASCs differentiation and plasticity. A gene expression profiling
..
.. study has demonstrated a differential time-dependent expression signa-
.. ture of pro- and anti-inflammatory cytokines between ASCs undergoing
..
.. osteogenic differentiation and ASCs undergoing adipogenic differenti-
.. ation.96 Some of the pro-inflammatory cytokines that showed an early
..
.. up-regulation in ASCs that are differentiating to osteoblasts, such as IL-1
.. and TNF-a, had been shown to suppress PPAR-c expression, thus in-
..
.. hibiting adipogenic differentiation.97 Obesity induces an important dysre-
.. gulation not only of adipocytes but also of ASCs plasticity98 that
..
.. contributes to the induction of adipocyte hypertrophy and hyperplasia
.. through the increase in pro-inflammatory cytokines.99 Therefore,
..
. the pro-inflammatory milieu that characterizes obesity and other
1068 L. Badimon and J. Cubedo

Figure 2 Impact of the pro-inflammatory state induced by metabolic disturbances on ASCs properties. The presence of metabolic disturbances such as
obesity and type-2-diabetes, leads to a pro-inflammatory state in AT depots inducing important changes in ASCs that affect their abilities. The image shows
the signalling pathways and/or effectors that have been proposed to be activated (red) or attenuated (green) under the inflammatory stimulus. Red arrows
indicate enhanced properties and green arrows diminished properties.

..
cardiovascular associated metabolic disturbances directly influences ..
ASCs plasticity by affecting their proliferation and differentiation poten- ..
..
tial, finally determining their regenerative potential (Figure 2). The under- ..
standing of the mechanisms by which inflammation affects ASCs ..
..
plasticity is crucial in order to be able to develop therapeutic approaches ..
based on autologous delivery of ASCs. Indeed, previous work of our ..
..
group has demonstrated a role for sphingosine kinase-1 (SK1) in the ..
regulation of the pro-inflammatory response in ASCs and a potential
..
..
therapeutic role of the targeted inhibition of this enzyme in the attenu-
ation of the chronic inflammatory state in obesity-related metabolic
disturbances.100
4.1 Effects on ASC differentiation and
proliferation
The potential of ASCs to differentiate, grow and proliferate is deter-
mined by the surrounding environment. Thus, the presence of metabolic
disturbances, such as that induced by obesity, can clearly affect ASCs dif-
ferentiation and proliferation capacity.
High-fat diet induction of obesity in an experimental pig model has
shown to induce increased circulating TNF-a levels, consistent with the
obesity-induced pro-inflammatory phenotype.101 Furthermore, ASCs
from obese animals showed increased senescence and an increased
adipogenic and osteogenic potential compared with ASCs from lean ani-
mals. Importantly, this animal model corresponded to a model of early
obesity without the clustering of other CVRFs that can influence ASCs
plasticity. Interestingly, we have described that ASCs from morbidly
obese patients obtained from SAT at the moment of bypass gastric sur-
gery revealed a lower proliferation and adipogenic differentiation poten-
tial compared with ASCs from non-obese subjects that underwent
liposuction.88 It is important to highlight, that morbidly obese patients
.. represent a late stage in the development of obesity where metabolic
.. syndrome is already established and where the pro-inflammatory signals
..
.. have been maintained for a long period. In fact, by using transcriptomic
.. approaches we have demonstrated that ASCs from morbidly obese pa-
..
.. tients loss their stemness showing a pre-adipocyte-like differentiated
.. phenotype, and that the impartment in the transcriptomic profile is
..
.. higher in ASCs from obese patients with metabolic syndrome and clus-
..
.. tering of several CVRFs than in ASCs from obese metabolically healthy
.. patients.87 Taken together these evidence underscore the additive effect
..
.. of each CVRF and metabolic disturbance on ASCs plasticity.
.. Besides affecting ASCs proliferative potential and differentiation pro-
..
.. file, metabolic disturbances affect other key properties of stem cells. As
.. such, ASCs from obese and type-2-diabetic patients have shown higher
..
.. migration, invasion and phagocytosis capacity than that from lean sub-
.. jects.102 These changes were accompanied by an increase in the
Inflammation, adipose tissue depots, and stem cells
..
expression of pro-inflammatory cytokines, such as IL-1b, IL-6, TNF-a
and monocyte chemoattractant protein (MCP-1), and the activation of
the NLRP3 (NOD- and pyrin domain-containing like receptor 3) inflam-
masome signalling pathway, which is associated to innate immunity.
Importantly, the increase in inflammatory markers was observed both in
VAT and SAT of obese and type-2-diabetic patients. The increase in mi-
gration, invasion and phagocytosis in ASCs from obese and type-2-
diabetic subjects was accompanied by a higher metabolic activity
(increased glycolytic phenotype, decreased succinate dehydrogenase ac-
tivity and increased succinate release) probably due to a high metabolic
ATP demand, comparable to that observed in cancerous cells. In fact,
the same authors found increased mRNA levels and activity of MMP-2
and MMP-9 in ASCs from obese and type-2-diabetic subjects.
Diabetes has also been shown to affect ASCs plasticity. By using a rat
model of diabetes, we have found a co-ordinated inhibition in the gene
expression profile of Notch, Wnt, and fibroblast growth factor (FGF) in
ASCs from SAT of diabetic rats compared with a non-diabetic control
group, together with an increased ASC-commitment to the adipogenic
lineage and a compromised self-renewal potential.91 Indeed, the activa-
tion of the Notch signalling pathway has been proposed as a key factor
determining the intrinsic expansion ability of different WAT depots.90
4.2 Effects on ASC functionality
Changes in the differentiation and proliferation potential of ASCs can
have a clear impact on their functionality and thus in their potential use
in regenerative medicine. However, inflammation and metabolic disturb-
ances also impair the main ASCs abilities for which they have been con-
sidered an important tool for regenerative therapies.
Among the described properties of ASCs, their pro-angiogenic func-
tion is one of the most important abilities in the context of cardiovascu-
lar regenerative medicine.103 This angiogenic potential of ASCs is
mediated through the release of paracrine factors. Indeed, we have seen
in an experimental pig model that co-administration of allogenic ASCs
and their conditioned media synergistically contribute to the neovascula-
rization of the infarcted myocardium as compared with the delivery of
conditioned media or ASC alone through a co-ordinated up-regulation
of the pro-angiogenic protein interactome.104 However, this ability may
be impaired in ASCs homed in obese AT, as we have demonstrated that
ASCs from SAT of morbidly obese patients secrete higher levels of the
anti-angiogenic factor TSP-1 than ASCs from lean individuals, and that
ASC-conditioned media from morbidly obese patients show a lower
pro-angiogenic capacity than that from lean subjects.88 In line with this
observation, ASCs obtained from SAT of diabetic rats show an impaired
ability to form microvessel networks in an in vivo plug angiogenesis assay
compared with a non-diabetic control group.91 Similarly, the presence of
a clustering of CVRFs in a rat model induces the loss of the pro-
angiogenic paracrine effects on endothelial cells of ASCs from epicardial
AT compared with that of rats without CVRFs.89 Interestingly, an over-
activation of the Notch signalling pathway was found to be responsible
for this cardiovascular risk-driven loss of ASC angiogenic potential.
These results underscore, an AT depot-specific role of Notch signalling
in the regulation of ASC angiogenic potential. Another key property of
ASCs is their high immunomodulatory activity that is even more potent
than that of other mesenchymal stem cells.105 Importantly, obesity also
blunts ASCs immunomodulatory capacities.102
These inflammation-mediated changes (Figure 2) could negatively influ-
ence ASCs regenerative potential limiting their functionality within AT
and their potential use in autologous cell-based therapy.
1069
.. 5. Reversibility of changes on AT
..
.. depots and resident ASCs
..
..
.. A key issue regarding ASCs plasticity is whether the detrimental effects
.. induced by stress conditions such as obesity or diabetes, can be reverted
..
.. or attenuated after the restoration of the metabolic phenotype. The
.. possibility of reversing the deleterious effects induced on ASCs would
..
.. be essential for the restoration of AT homeostasis and could represent a
.. promising approach for their use in autologous cell-based regenerative
..
.. therapies. In this regard, weight loss (WL) strategies have revealed a cer-
.. tain reversibility of obesity-associated AT changes by acting at different
..
.. levels: (i) inducing structural changes in AT depots and adipocytes;
.. (ii) partly reversing the pro-inflammatory status; (iii) changing the adipo-
..
.. kine profile; and (iv) restoring ASCs functionality.
..
..
.. 5.1 AT structural changes
..
.. WL induces different changes in the gene expression profile of both
.. depots evidencing once more the differences in the plasticity between
..
.. VAT and SAT.106,107 Interestingly, a recent meta-analysis evaluating all
.. available studies analysing the effect of different WL strategies (diet, ex-
..
.. ercise, pharmacologic treatment, and bariatric surgery) has revealed that
.. although SAT loss is greater than VAT loss, the percent of change is
..
.. higher in VAT than in SAT.108 There is also evidence of a time-
.. dependent effect in the differential fat loss between both depots, being
..
.. SAT changes associated to short term WL after bariatric surgery,109
.. whereas VAT decline is more evident in longer follow-up studies.110 In
..
.. both depots, fat loss seems to be proportional to BMI decrease, in nor-
..
.. mal weight, obese and severely obese subjects, and is associated with a
.. reduction in insulin plasma levels and an improved homeostatic model
..
.. assessment (HOMA) index.111 Thus, the decrease in visceral and sub-
.. cutaneous fat depots induced by WL is able to restore, at least in part,
..
.. the AT metabolic homeostasis. WL in severely obese individuals has also
.. shown to revert some of the obesity-associated changes in epicardial AT
..
.. by reducing tissue thickness.112 A recent study using advanced MRI tech-
.. nology113 has revealed that bariatric surgery is associated with a reduc-
..
.. tion of subcutaneous, visceral and epicardial fat at 6-month follow-up.
.. A crucial event behind the beneficial effects of WL is the reduction in
..
.. adipocyte hypertrophy. Patients undergoing bariatric surgery have
.. shown a significant decrease in adipocyte size reaching a diameter similar
..
.. to that of lean controls but without changes in adipocyte numbers.114,115
.. Importantly, the reduction in adipocyte size is correlated with the im-
..
.. provements in insulin sensitivity even at the long term follow-up after
.. the surgery.115 However, the exact intracellular mechanism leading to
..
.. the decrease in adipocyte size after surgery is yet unknown.
..
..
.. 5.2 Reversibility of the pro-inflammatory
..
.. status
..
.. A key feature in the reversible nature of obesity-induced changes in AT
.. is the attenuation of inflammatory and immune pathways both in SAT
..
.. and VAT. Specifically, WL has been associated with an improvement of
.. the pro-inflammatory state in SAT116,117 with a decrease in inflammatory
..
.. cytokines and immune cells infiltration.118,119 Systemic levels of two im-
.. portant pro-inflammatory cytokines, IL-6 and MCP-1, have been consist-
..
.. ently shown to decrease in obese patients after surgery, together with a
.. significant decrease in the genes expression of these cytokines in AT
..
.. depots. Similarly, circulating levels of CRP are also decreased after sur-
.. gery being this decrease still evident after 10-years follow-up.120,121 This
..
. decrease in CRP levels has been associated to an improvement in
1070 L. Badimon and J. Cubedo

..
cardiovascular risk. Importantly, these changes in pro-inflammatory cyto- .. 6. Concluding remarks
kines after WL seem to have an impact on AT infiltrated macrophages ..
.. AT is a highly heterogeneous organ and its physiological functionality de-
with a shift in the balance pro-/anti-inflammatory macrophages after bari- ..
atric surgery.122 .. pendents on the interactions between adipocytes and the cells of the
.. stromal fraction.135 The dysregulation of these interactions by the pres-
All these observations undoubtedly support that WL attenuates the ..
pro-inflammatory profile induced by obesity. .. ence of individual conditioning factors (age, CVRFs, etc.) leads to AT dys-
..
.. function and metabolic disturbances. AT heterogeneity gets even more
.. complex when ASCs are considered. Indeed, experimental studies using
5.3 Changes in adipokine secretion profile ..
A hallmark of healthy AT function is its adipokine secretion profile which
.. ASCs from both animals and humans have proved that ASCs plasticity
.. appears as a key driver of the inherent differences in the expansion
is significantly altered in obesity. WL due to bariatric surgery has shown ..
.. capacities of different AT depots.83
to restore the healthy adipokine secretion by increasing adiponectin and .. The identification of the key mechanisms that trigger the restoration
decreasing leptin levels123,124 pointing out to a regain in AT endocrine ..
.. of AT metabolic function and the reversion of the obesity-associated
function. Even normalization in the secretion of other less studied adipo- .. pro-inflammatory state by the application of WL approaches would help
kines, such as visfatin and chemerin, has also been reported.125,126 ..
.. to develop novel therapeutic strategies for obesity and metabolic dis-
Importantly, it has been shown that changes in adiponectin occur before .. eases. Among these potential mechanisms the restoration of ASCs func-
a significant WL can be observed suggesting that the shift in adipokine se- ..
.. tionality could play an essential role in regaining the healthy AT
cretion profile is not dependent on fat loss.127 .. phenotype. In this context, further research is needed in order to delin-
All these evidence point out towards an important role of the WL- ..
.. eate the exact mechanism governing ASCs plasticity.
mediated restoration of adipokine secretion profile and the metabolic ..
improvements observed in AT. ..
..
..
.. Acknowledgements
5.4 Influence of ASCs plasticity ..
.. This work has been supported by grants to L.B. from the Spanish
WL-mediated effects on ASCs could be one of the mechanisms behind .. Ministry of Economy and Competitiveness of Science [SAF2016-76819-
the reversibility of obesity-related AT changes. However, contradictory ..
.. R]; Institute of Health Carlos III, ISCIII [TERCEL RD16/0011/0018 and
findings have been reported regarding the relation between WL and the .. Ciber CB16/11/0041]; FEDER ‘Una Manera de Hacer Europa’; the
recovery of ASCs properties. It has been described that obese subjects ..
.. Secretary of University and Research, Department of Economy and
under long-term calorie restriction show ASCs with reduced DNA dam- .. Knowledge of the Government of Catalonia [2014SGR1303]; and
age and improved survival compared with ASCs from obese subjects, ..
.. ‘CERCA Programme/Generalitat de Catalunya’ Spain.
without affecting their adipogenic capacity.128 Contrarily, a superior ..
in vitro adipogenic potential has been reported for ASCs isolated from .. Conflict of interest: none declared.
..
subjects who formerly had obesity when compared with non-obese indi- ..
viduals.129 However, complete WL has to be analysed cautiously when ..
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