Cell Metabolism

Previews
Grotthuss, M., Fontanillas, P., Spooner, A., et al.;
MEDIA Consortium; SIGMA T2D Consortium
(2017). Type 2 diabetes variants disrupt function
of SLC16A11 through two distinct mechanisms.
Cell 170, 199–212.e20.
Williams, A.L., Jacobs, S.B., Moreno-Macı́as, H.,
Huerta-Chagoya, A., Churchhouse, C., Márquez-
Luna, C., Garcı́a-Ortı́z, H., Gómez-Vázquez, M.J.,
Burtt, N.P., Aguilar-Salinas, C.A., et al.; SIGMA
Type 2 Diabetes Consortium (2014). Sequence
variants in SLC16A11 are a common risk factor
for type 2 diabetes in Mexico. Nature 506, 97–101.
Williamson, D.H., Lund, P., and Krebs, H.A. (1967).
The redox state of free nicotinamide-adenine dinu-
cleotide in the cytoplasm and mitochondria of rat
liver. Biochem. J. 103, 514–527.
Yoshino, J., Mills, K.F., Yoon, M.J., and Imai, S.
(2011). Nicotinamide mononucleotide, a key
NAD(+) intermediate, treats the pathophysiology
of diet- and age-induced diabetes in mice. Cell
Metab. 14, 528–536.
Yoshino, J., Baur, J.A., and Imai, S.I. (2018). NAD+
intermediates: the biology and therapeutic poten-
tial of NMN and NR. Cell Metab. 27, 513–528.

Vascular Organoids: Are We Entering

a New Area of Cardiometabolic Research?
Tyler T. Cooper,1,2 David A. Hess,1,2,3,5,* and Subodh Verma4,5,6,7
1Robarts Research Institute, Western University, London, ON, Canada
2Department of Physiology and Pharmacology, Western University, London, ON, Canada
3Division of Vascular Surgery, St Michael’s Hospital, Toronto, ON, Canada
4Division of Cardiac Surgery, St Michael’s Hospital, Toronto, ON, Canada
5Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
6Institute of Medical Science, University of Toronto, Toronto, ON, Canada
7Department of Surgery, University of Toronto, Toronto, ON, Canada

*Correspondence: dhess@robarts.ca
https://doi.org/10.1016/j.cmet.2019.03.008

Recently in Nature, Wimmer et al. (2019) reported on the development of a human organoid model of vascular
development recapitulating vascular pathology during type 2 diabetes. Integration of these organoids into
the vasculature of immunodeficient mice may provide cardiometabolic researchers with a ‘‘personalized’’
platform for novel therapeutic discovery.

Cardiometabolic syndromes (CMSs)
manifest as a spectrum of imbalances
that compromise cardiovascular health,
including impaired glycemic regulation
(i.e., diabetes), dyslipidemia (i.e., obesity),
and hypertension (Cirulli et al., 2019). Like-
wise, the etiology of CMS is linked to
patient-dependent risk factors (i.e., ge-
netic, epigenetic, and environmental) that
contribute to the deterioration of cardio-
vascular health in both synergistic and in-
dependent modalities. The prevalence of
CMS is currently >400 million individuals
globally and is driven by an epidemic
surge of obesity and type 2 diabetes
(T2D), burdening the international health-
care system with an estimated cost of
725 billion USD in 2017 (International
Diabetes Federation, 2018). Risk for life-
threating cardiovascular comorbidities,
such as stroke, myocardial infarction, or
peripheral artery disease, is increased
5-fold in T2D patients alone. Decades of
pre-clinical CMS research have led to the
development of therapeutic strategies
that primarily aim to mitigate inflammation
and disease progression, improve patient
quality of life, or bypass occluded vascula-
ture to oxygenate ischemic tissues.
Unfortunately, many biotherapeutic stra-
tegies that demonstrated therapeutic ben-
efits in pre-clinical studies have failed to
translate into clinical efficacy (Perin et al.,
2017), indicating that novel pre-clinical
systems to evaluate therapeutic efficacy
are critically warranted. For these reasons,
human-derived blood vessel organoids,
recently characterized by the Penninger
group (Wimmer et al., 2019), represent a
promising ‘‘humanized bridge’’ to propel
pre-clinical research toward novel thera-
peutics to target reversal of cardiometa-
bolic syndromes and resultant cardiovas-
cular deterioration (Figure 1).
Inflammation of microvascular net-
works underlies a spectrum of tissue
pathology observed in diabetes and
its related cardiovascular ailments (Siti
et al., 2015). At the root of inflammation
are metabolic imbalances that manifest
when damaging oxidative byproducts
and reactive oxygen species (ROS) are
generated due to chronic hyperglycemia
or hyperlipidemia. Elevated levels of
damaging metabolites lead to the dys-
regulation of anti-oxidative pathways,
reduced endothelial nitric oxide produc-
tion, atherosclerotic plaque formation,
and collapse of functional microvascular
architecture. Therefore, it is imperative
that preclinical models can (1) accurately
mimic the pathophysiology of human
CMS and (2) robustly integrate a diversity
of patient-specific pathology and risk fac-
tors encountered clinically. For decades,
murine models have attempted to recapit-
ulate human cardiovascular development
and cardiovascular pathology. However,
many factors limit the translation of
murine models to human CMS. Although
95% of the murine protein-coding
genome shares homology with humans,
non-protein-coding genes or regulatory
loci are comparably distinct between spe-
cies (von Scheidt et al., 2017). Regions of

792 Cell Metabolism 29, April 2, 2019 ª 2019 Published by Elsevier Inc.
Cell Metabolism

Previews

Figure 1. Patient-Derived Vascular Organoids Provide a Novel Platform for Cardiometabolic Research
Vascular organoids have the potential to be derived from healthy patients or those suffering from cardiometabolic disorders and/or cardiovascular disease
through the generation of induced pluripotent stem cells. Organoids subjected to culture conditions that mimic cardiometabolic disorders would allow a
‘‘personalized’’ model for the discovery of novel therapeutics.

non-protein-coding DNA, which provide
post-transcriptional/translational regula-
tion of inflammatory pathways, become
dysregulated in human CMSs that may
not be conserved in murine models. For
example, miR146a functions to suppress
pro-inflammatory NF-kB signaling axis in
endothelial cells in an effort to mitigate
inflammation, atherosclerotic lipoprotein
production, and plaque formation (Cheng
et al., 2017). Murine cardiovascular net-
works, when exposed to a Western
diet, demonstrate considerable resis-
tance to elevated atherogenic lipopro-
teins, and advanced atherosclerotic
plaque and lesion formation are nearly
impossible without genetic perturbations,
such as apolipoprotein E (Apoe / ) or
LDL receptor (Ldlr / ) knockout models.
Although these models corroborate clin-
ical risk factors observed in humans,
atherosclerosis in mice lacks pathological
hallmarks of human pathology (von
Scheidt et al., 2017). Lesion development,
plaque complexity, localization to coro-
nary arteries, intimal thickening, and
thrombotic plaques observed in human

Cell Metabolism 29, April 2, 2019 793


patients are not mimicked in mice. Finally,
most fatal cardiovascular complications
arise from thrombosis formation; thus, a
need for accurate models of human path-
ophysiology persists. Therefore, resolving
inter-species variation by utilizing human
tissue-derived vascular models currently
presents invaluable potential to effectively
accelerate the translation of pre-clinical
research toward novel therapeutic and
biomarker discovery.
Over the last decade, human organoid
models have emerged to the forefront
of pre-clinical research as potentially
insightful means to study human develop-
ment or tissue pathophysiology (Clevers,
2016). Wimmer et al. recently addressed
two persistent deficiencies of organoids
for vascular research: (1) tissue organoids
were devoid of functional and perfused
vasculature, limiting the maturation and or-
ganization of the organoid systems, and (2)
there has been limited scalability for high-
throughput drug screening. Organoid
vasculature assembly and integration
have been previously reported. Zhang
et al. demonstrated an ‘‘AngioChip’’ perfu-
sion system could support development of
human cardiac and hepatic tissue that
could be subsequently transplanted into
rodent models (Zhang et al., 2016). Artifi-
cial perfusion networks were lined with
endothelial cells capable of drug delivery
to cultured parenchyma and permitted
leukocyte extravasation. This approach,
among others, has demonstrated the
immense potential of human-derived or-
ganoid cultures to study cardiometabolic
disorders in complex tissues. At the cur-
rent state, it is reasonable to envision the
development of organoid systems will (1)
vastly improve our understanding of cardi-
ometabolic pathology and (2) serve as a
biotherapeutic tool to combat life-threat-
ening microvascular comorbidities.
Recently, the Penninger lab has pro-
vided pivotal insight into generation of 3D
vascular organoids that spontaneously
anastomosed into a perfused vascular
tree when transplanted into the kidney
capsule of NOD/SCID IL-2Rg null (NSG)
mice (Wimmer et al., 2019). These organo-
ids self-assembled into hierarchal capillary
networks in vitro, including arterial to
794 Cell Metabolism 29, April 2, 2019
venous anastomoses and mature endo-
thelial protein (von Willebrand factor)
expression. Organoid vessel networks
were enveloped by a basement mem-
brane supported by PDGRB+/NG2+
smooth muscle cells or pericytes, and in-
traluminal detection of human CD45+ he-
matopoietic progeny was also observed.
Because 30% of individuals with diabetes
develop vasculopathy, leading to often
fatal macrovascular and microvascular
complications, organoids were challenged
using an in vitro system (hyperglycemia
with IL-6 + TNF) that mimicked microenvi-
ronmental changes in T2D. Under these
conditions, organoid vessels demon-
strated an increase in subendothelial
collagen IV deposition, smooth muscle
cell proliferation, loss of vascular tone,
and increased endothelial cell perme-
ability. The organoids also supported
high-throughput drug screening in vitro
(i.e., 96-well format) and were used to
discover that the DLL4/NOTCH3/Hes5
signaling axis acts as a driver of
aberrant type IV collagen expression in
both ‘‘diabetic’’ organoids and clinical dia-
betes. Diabetic organoids cultured with
y-secretase inhibitor (DAPT) demon-
strated reduced Hes5 expression in
smooth muscle cells, in turn reversing
pathophysiology reflective of clinical dia-
betic vasculopathy and microvascular
inflammation. Remarkably, vascular orga-
noids that underwent xenotransplantation
into streptozotocin-treated NSG mice
retained a pathological phenotype, such
as vessel regression, reflective of a com-
mon microvascular co-morbidity in indi-
viduals with T2D.
In summary, there is exciting potential
for human-derived vascular organoids to
shift the therapeutic discovery paradigm,
which has been primarily dependent on
genetically modified murine models, to-
ward ‘‘personalized’’ patient-derived or-
ganoids that replicate cardiometabolic
disorders. However, a reproducible and
systematic approach will be necessary
to determine the pre-clinical value of
vascular organoids in the development
of novel drugs and future strategies to
combat macro- and microvascular pa-
thologies observed with CMS.
Cell Metabolism
Previews
DECLARATION OF INTERESTS
S.V. holds a Tier 1 Canada Research Chair in
Cardiovascular Surgery, and reports receiving
research grants and/or speaking honoraria from
Amgen, AstraZeneca, Bayer Healthcare, Boeh-
ringer Ingelheim, Eli Lilly, Janssen, Merck, Novar-
tis, Novo Nordisk, Sanofi, Servier, and Valeant.
He is also the President of the Canadian Medical
and Surgical Knowledge Translation Research
Group, a federally incorporated not-for-profit
physician organization. All other authors declare
that they have no relevant disclosures.
REFERENCES
Cheng, H.S., Besla, R., Li, A., Chen, Z., Shikatani,
E.A., Nazari-Jahantigh, M., Hammoutène, A.,
Nguyen, M.-A., Geoffrion, M., Cai, L., et al.
(2017). Paradoxical suppression of atherosclerosis
in the absence of microRNA-146a. Circ. Res. 121,
354–367.
Cirulli, E.T., Guo, L., Leon Swisher, C., Shah, N.,
Huang, L., Napier, L.A., Kirkness, E.F., Spector,
T.D., Caskey, C.T., Thorens, B., et al. (2019).
Profound perturbation of the metabolome in
obesity is associated with health risk. Cell Metab.
29, 488–500.e2.
Clevers, H. (2016). Modeling development and dis-
ease with organoids. Cell 165, 1586–1597.
International Diabetes Federation (2018). IDF
Diabetes Atlas (International Diabetes Federation).
Perin, E.C., Murphy, M.P., March, K.L., Bolli, R.,
Loughran, J., Yang, P.C., Leeper, N.J., Dalman,
R.L., Alexander, J., Henry, T.D., et al.;
Cardiovascular Cell Therapy Research Network
(CCTRN) (2017). Evaluation of cell therapy on
exercise performance and limb perfusion in
peripheral artery disease: the CCTRN PACE
trial (patients with intermittent claudication in-
jected with ALDH bright cells). Circulation 135,
1417–1428.
Siti, H.N., Kamisah, Y., and Kamsiah, J. (2015). The
role of oxidative stress, antioxidants and vascular
inflammation in cardiovascular disease (a review).
Vascul. Pharmacol. 71, 40–56.
von Scheidt, M., Zhao, Y., Kurt, Z., Pan, C., Zeng,
L., Yang, X., Schunkert, H., and Lusis, A.J.
(2017). Applications and limitations of mouse
models for understanding human atherosclerosis.
Cell Metab. 25, 248–261.
Wimmer, R.A., Leopoldi, A., Aichinger, M., Wick, N.,
Hantusch, B., Novatchkova, M., Taubenschmid, J.,
Ha€mmerle, M., Esk, C., Bagley, J.A., et al. (2019).
Human blood vessel organoids as a model of
diabetic vasculopathy. Nature 565, 505–510.
Zhang, B., Montgomery, M., Chamberlain, M.D.,
Ogawa, S., Korolj, A., Pahnke, A., Wells, L.A.,
Massé, S., Kim, J., Reis, L., et al. (2016).
Biodegradable scaffold with built-in vasculature
for organ-on-a-chip engineering and direct surgi-
cal anastomosis. Nat. Mater. 15, 669–678.