V.III. Combined effect of MSC and GLP-1 based drugs
Multipotent mesenchymal stem cell (MSC) based therapy may apply to lung
injuries including ALI and radiation-induced lung injury, as well as
other disorders (142-147). More than 18 years ago, Ortiz and colleagues
have demonstrated that when male mouse bone marrow derived MSCs were
intravenously administrated, they were able to home to the recipient
female mouse lung in response to bleomycin-induced injury (148). Those
MSCs were shown to adopt an epithelium-like phenotype, reducing both
inflammation and collagen deposition (148). Mechanistic exploration
studies have then demonstrated that those MSCs can produce paracrine
factors, such as IL-1 receptor antagonist (IL-1RA), IL-10, keratinocyte
growth factor (KGF), and prostaglandin E2 (146, 149). In LPS challenge
induced ALI mouse model, Mei and colleagues demonstrated that
bone-marrow derived MSCs with overexpressed angiopoietin 1 (Agn-1)
further reduced the severity of lung injury (150). Gupta and colleagues
then demonstrated that in LPS-induced ALI mouse model, intrapulmonary
delivery of bone marrow-derived MSCs four hours after LPS-challenge was
still able to improve survival and attenuate lung injury (151). During
the last decade, functions of MSCs from various sources including bone
marrow, adipose tissue, lung tissue, as well as human chorionic villi
were also assessed in multiple disease models. For studies on additional
paracrine factors released by MSCs and mechanistic exploration on MSC
therapy in lung injuries, please see review articles elsewhere
(152-155). In below we will only discuss recent studies that involve
GLP-1 and GLP-1R.
In 2010, Sanz and colleagues reported the detection of GLP-1R in hMSC,
derived from bone marrow. They found that in hMSC, GLP-1 treatment
stimulated cell proliferation and reduced cell apoptosis. Furthermore,
GLP-1 treatment prevented cell differentiation into adipocytes,
associated with the repression of peroxisome proliferator-activated
receptor-γ (PPARγ), C/EBPβ, and lipoprotein lipase (LPL) (156). A few
studies then tested the effect of combined use of MSC and GLP-1 in
myocardial infarction (157-159). MSC with GLP-1 conditioned media were
shown to possess antiapoptotic effects on ischaemic human cardiomyocytes
(159). MSCs that engineered to secrete a GLP-1 fusion protein were shown
to possess therapeutic effects in myocardial infarction in a pig model
(157, 159).
More recently, attempts have also been made in testing combined use of
hMSC and liraglutide in ALI mouse model (160, 161). Last year, Yang and
colleagues reported that LPS treatment could attenuate proliferation of
human chorionic villus-derived MSCs (hCMSCs), human bone marrow-derived
MSCs (hBMSCs), and human adipose-derived MSCs (hAMSCs). In LPS-induced
ALI mouse model, liraglutide combined with MSCs showed a more
significant therapeutic effect (160). Dose dependent reduction effect of
LPS on hCMSC proliferation and expression of GLP-1R, Ang-1 and FGF-10
were then demonstrated in another study conducted by the same group by
Fang and colleagues (161). Furthermore, the study by Fang and colleagues
demonstrated that liraglutide treatment dampened the above reductions,
involving the cAMP/PKAc/β-catenin-TCF4 signaling pathway. The same study
also reported that combined use of liraglutide and hCMSCs exhibited
enhanced therapeutic efficacy than liraglutide alone in reducing lung
injury in their mouse ALI model (161).
Conclusion and perspectives
Shortly after the clinical utilization of GLP-1-based drugs in patients
with T2D, the anti-inflammatory features of them were immediately
observed. As chronic inflammation contributes to the pathobiology and
etiology of T2D, these observations have further expanded our
mechanistic understanding on the therapeutic functions of GLP-1R
agonists. Importantly, these observations have triggered intensive
exploration of anti-inflammatory features of GLP-1 based drugs in
general and in translational investigations, aiming to repurpose them
for other inflammation related disorders.
In this review, we have discussed both clinical and pre-clinical
investigations on the anti-inflammatory and immune cell modulatory
features of GLP-1R agonists. Importantly, we commented on the
controversy regarding direct in vitro effect of GLP-1R agonist
treatment in immune cells. We have discussed that the in vivorepressive effect of liraglutide treatment on expression of inflammatory
genes in PBMCs were not recaptured in the in vitro settings with
direct liraglutide treatment in THP-1 and primary PBMCs by Zobel and
colleagues, and they cannot detect GLP-1R in those immune cells (84).
Thus, it remains to be determined whether GLP-1 based drugs exert their
anti-inflammatory and immune modulatory functions via indirect
mechanisms. This could involve a brain-peripheral tissue axis, or via
interacting with a small specific portion of immune cells that do
express GLP-1R. Indeed, a study by Yusta and colleagues in 2015 showed
that GLP-1R expression is enriched in intestinal intraepithelial
lymphocytes (IEL) (162). In mouse adipose tissues, GLP-1R expression is
known to be enriched in stromal vascular fraction (SVF) (97). Very
recently, McLean and colleagues have located GLP-1R expression in the
liver in a small portion of T lymphocytes (γδ cells). They reported that
metabolic and anti-inflammatory effect of semaglutide treatment observed
in wild type mice were absent or attenuated inGlp1rTie2-/- mice (163). Hence Tie2-targeted
GLP-1R+ cells are required for a subset of the anti-inflammatory actions
of semaglutide in the liver, and possibly elsewhere (163). It appears
that the regulatory effect of liraglutide treatment on blood pressure is
also mediated by a small portion of GLP-1R expressing cells in mouse
cardiac atria, followed by sending signal to produce ANP (79).
GLP-1R is most abundantly expressed in mouse lung, demonstrated 25 years
ago by Bullock and colleague, with the classical methods including RNAse
protection, RT-PCR, and in situ hybridization (102). This
investigation has also denied GLP-1R expression in adipose, liver, and
skeletal muscle (102). As lung GLP-1R level elevated 4 times on the
first day of birth, and elevated plasma GLP-1 level was observed in
patients with systematic inflammation such as severe burn injury, it is
likely that GLP-1 and lung GLP-1R represent a yet to be further explored
defense system of our body. Observations made in a few clinical trials
and retrospective studies have supported the beneficial effect of GLP-1
based drugs in asthma and lung injury. Detailed understanding of this
defense system and properly utilizing the tools in regulating this
system may allow us to treat both chronic and acute lung injuries.
The key inflammasome component TxNIP, a known therapeutic target of
diabetes, is also among the major targets of GLP-1/GLP-1R signaling
pathway activation in the lung. Lung TxNIP elevation can be stimulated
by plasma glucose level elevation or the release of the stress hormone
glucocorticoid (103), which is a recognized double-edged sword in ARDS
treatment. Whether a moderate stimulation on lung TxNIP elevation in
response to glucose and glucocorticoid elevation also represents a
defensive response remains to be investigated. It is also worth to
determine whether TxNIP knockout brings beneficial or deleterious
outcome in mice with LPS or other inflammatory challenges.
Both nanomedicine and hMSC-based cell therapy are the cutting-edge
skills in translational medicine. GLP-1-SSM, a putative nanomedicine
tool has already been tested in ALI model and in bowl inflammation
model, while combined hMSC and GLP-1 based drugs have been studied in a
pig myocardial infarction model; and more recently, in the mouse ALI
model. We anticipate seeing further development of the application of
these two “therapies” in preclinical studies and in clinical trials in
the near future.
The whole world has bene undergoing the astonishing Covid-19 pandemic.
There are literatures debating on whether GLP-1-based drugs may serve as
a cure or adjuvant for Covid-19 treatment (132, 133, 164, 165). A recent
meta-analysis conducted by Hariyanto and colleagues covered nine studies
with 19,660 patients of T2D who were infected by SARS-CoV-2 (166). The
study suggested that pre-admission of GLP-1-based drugs was associated
with reduced mortality rate (166). Further retrospective studies and
pre-clinical studies should be conducted to determine the therapeutic
and preventative potential of GLP-1R agonists on Covid-19 animal models,
as our battle with such pandemic is likely a long journey.