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Current Stem Cell Research & Therapy, 2021, 16, 608-621

REVIEW ARTICLE
ISSN: 1574-888X
eISSN: 2212-3946

Current Stem Cell

Research & Therapy

Mesenchymal Stem Cell Therapy for Patients with Ischemic Heart Fail- Impact
Factor:
2.614

ure-Past, Present, and Future

BENTHAM
SCIENCE

Peng Liang1,#, Fang Ye1,#, Cong-Cong Hou1, Lin Pi1 and Fang Chen1,*

Department of Cardiology, Chui Yang Liu Hospital, Tsinghua University, Beijing 110105, China

Abstract: The prevalence of Heart Failure (HF) has increased over time. Ischemic heart failure ac-
counts for 50% of HF, which results from ischemic coronary heart diseases such as Myocardial Infarc-
ARTICLE HISTORY tion (MI). Conventionally, reduction of cardiac load and revascularization partially increase cardio-
myocyte survival and preserve cardiac functions. Nevertheless, how to improve cardiomyocyte rescue
Current Stem Cell Research & Therapy

Received: August 29, 2019
Revised: October 24, 2019
Accepted: December 19, 2019
DOI:
10.2174/1574888X15666200309144906
and prevent HF progression remain as challenges. Mesenchymal Stem Cells (MSCs) are multipotent
stem cells that give rise to various lineages. The administration of MSCs promotes cardiomyocyte sur-
vival and improves cardiac functions in animal models of MI and patients with ischemic cardiomyopa-
thy. However, after injection, MSCs persist for a very short time, indicating that the prolonged protec-
tive effects of MSCs on cardiomyocytes may be mediated by paracrine functions of MSCs, such as
exosomes. In this review, we focus on MSC-derived exosomes in cardiomyocyte protection to facilitate
future applications of exosomes in HF treatment.

Keywords: Heart failure, ischemic cardiomyopathy, mesenchymal stem cells, exosomes, cardiomyocytes, myocardial infarction.

1. INTRODUCTION indicate that the occurrence of atrial fibrillation is less, but

A report from the American Heart Association suggests
that the overall prevalence of Cardiovascular Diseases
(CVDs), including Coronary Heart Disease (CHD), Heart
Failure (HF), stroke, and hypertension, is 48% in adults
aged ≥20 years, indicating that there are 121.5 million pa-
tients worldwide. CVD prevalence excluding hypertension
(CHD, HF, and stroke) is 9% (24.3 million in 2016). Ac-
cording to this report, an estimated 6.2 million Americans
aged ≥20 years had HF and the prevalence of HF will in-
crease to 46% from 2012 to 2030, resulting in more than 8
million patients by 2030 [1].
HF is the main cause of mortality, resulting from CVD.
There are two main types, HF with a reduced Ejection Frac-
tion (HFrEF) and HF with a preserved Ejection Fraction
(HFpEF), which are defined by left Ventricular Ejection Frac-
tions (LVEFs) of ≤50% or >50%, respectively. When com-
paring clinical features, patients with HFrEF are younger and
there are more prevalences of males, coronary heart disease,
and diabetes, who display a lower systolic blood pressure and
higher a heart rate and serum potassium levels compared
with HFpEF patients. Electrocardiogram characteristics
*Address correspondence to this author at the Department of Cardiology,
Chui Yang Liu Hospital, Tsinghua University, Beijing 110105, China;
Tel: +86 13501361615; Fax: +86 1067720012;
E-mail: anzhenchenfang@163.com
#
These authors contributed equally to this work.
ST-segment elevation and T-wave inversion are more fre-
quently seen in patients with HFrEF in comparison with
HFpEF patients [2, 3]. Moreover, in a retrospective study
involving 8833 HF patients, multivariate-adjusted Cox re-
gression showed that the risk of mortality was 13% higher
for HFrEF patients than HFpEF patients [4].
Aging, hypertension, diabetes, hyperlipidemia, and athe-
rosclerotic disease are common risk factors for HF. Data
from the National Health and Nutrition Examination Survey
have demonstrated that the prevalence of HF is 1.5% for
men at 40–59 years of age and 6.6% for men at 60-79 years
of age, which increases to 10.6% for men at ≥80 years of
age [5]. In a pooled cohort study, 19, 249 participants aged
45 years and 23, 915 participants aged 55 years were fol-
lowed up for 27.1 and 20.3 years, respectively, among
which 53.2% and 43.7% of participants had no hyperten-
sion, obesity, or diabetes. Following an HF incident, the
survival time of participants aged 45 years with three risk
factors was 9.8 and 13.0 years less for men and women,
respectively, compared with patients without hypertension,
obesity, and diabetes. Further dissecting the effect of each
individual risk factor on HF illustrated that survival time
after HF for men aged 45 years was reduced to 4.0 years for
patients with hypertension, 2.8 years for patients with obe-
sity, and 6.5 years for patients with diabetes. Similar find-
ings were obtained for female participants: the survival time
was 3.7, 3.4 and 8.8 years shorter for patients with hyper-

2212-3946/21 $65.00+.00 © 2021 Bentham Science Publishers

MSC Therapy for Ischemic Heart Failure Patients
tension, obesity, and diabetes, respectively, compared with
corresponding controls [6].
Based on the etiology, HF is categorized into non-
ischemic and ischemic HF [7]. Despite advances in the treat-
ment of CHD using medicines, percutaneous coronary
intervention, and bypass surgery, ischemic heart failure re-
sulting from coronary heart disease still has a poor progno-
sis with 40%-50% mortality by 5 years [8]. Cardiomyocytes
are the primary heart cells with a very limited proliferation
potential. Stem Cells (SCs) are ubiquitous and uncommitted
cell populations. Under optimal conditions, stem cells can
be directly differentiated into functional cardiomyocytes or
indirectly promote cell survival via secreted exosomes [9].
Thus, stem cell-derived cardiomyocytes provide a promising
means to replace dead cardiomyocytes to restore cardiac
functions. In this review, we discuss the current status of
treatments for ischemic heart failure, and the efficiency and
recent advances of Mesenchymal Stem Cell (MSC) therapy
and MSC-derived exosomes for cardiomyocyte protection in
the treatment of IHF.
2. MECHANISMS OF ISCHEMIC HF
Physically, efficient diastolic filling is highly dependent
on cardiomyocyte relaxation and the passive property of the
heart. Calcium is released from the sarcoplasmic reticulum
via the ryanodine receptor, and the increased intracellular
Ca2+ concentration activates cardiac contraction. During
diastole, Ca2+ is extruded from the cytosol back to the SR
via SERCa2a (Sarco/endoplasmic reticulum Ca2+-ATPase)
and sequestered there [10]. Thus, calcium homeostasis is
crucial to coordinate cardiac contraction and relaxation.
Myocardial infarction impairs calcium homeostasis and re-
sults in the abnormal diastolic filling.
STAT3 restrains Ca2+ release from the endoplasmic re-
ticulum and thus reduces overloading Ca2+ in mitochondria
[11]. Coronary arteries provide nutrient and oxygen supplies
for cardiomyocytes. In addition, coronary endothelial cells
and cardiomyocytes are in close communication to preserve
cardiac functions. For example, redox gene STAT3 is an
important messenger in this communication. As a redox
gene, STAT3 preserves mitochondrial integrity, restricts
reactive oxygen species formation, and regulates the expres-
sion of target genes such as ErbB and Bcl-xL in cardiomyo-
cytes. STAT3 expression is reduced in infarcted cardiomyo-
cytes, promoting cell death and fibrosis [11].
Following the blockade of blood flow-induced myocar-
dial infarction, apoptotic cardiomyocytes and activated en-
dothelial cells attract inflammatory cells infiltrating into the
injured site for clearance. When macrophages digest apop-
totic cells, they produce various inflammatory cytokines,
including IL-1β, IL-6, TNFα, and TGF-β. Following car-
diomyocyte apoptosis, fibroblasts transition to myofibro-
blasts, and activated myofibroblasts in the apoptotic border
zone produce a series of inflammatory cytokines and MMPs
to assist cardiac fibrosis. Activation of TGF-β in myofibro-
blasts induces fibrosis. The inflammatory cytokines increase
cardiomyocyte apoptosis with impaired autophagy as well
as activation of fibrosis, leading to cardiac hypertrophy [12].
In concert with the remodeling of extracellular matrix pro-
teins, dead cardiomyocytes are replaced by scar formation.
Current Stem Cell Research & Therapy, 2021, Vol. 16, No. 5 609
As the inflammation persists, lymphocytes and macrophages
continue to home to the scar, strengthening cardiac remodel-
ing and decreasing cardiac functions, leading to HF [13-15].
The underlying mechanisms of cardiomyocyte death in HF
are summarized in Fig. (1).
3. CURRENT STATUS OF TREATMENTS FOR
ISCHEMIC HEART FAILURE
Conventionally, treatments of ischemic HF include gen-
eral/basal treatments, agents, devices, and surgical interven-
tion. For basal treatment, patients are subjected to lipid and
sodium restriction (<3 g/d) as well as water restriction (<2
l/d). Aldosterone receptor antagonists, renin-angiotensin
system inhibitors, and β-blockers are administered to inhibit
ventricular remodeling and reduce the mortality of HF pa-
tients [16-22] as well as diuretics to reduce the symptoms of
congestion [23]. The PARADIGM-HF trial showed that the
blockade of the RAAS system by sacubitril/valsartan de-
creases the risk of the primary composite endpoint by 20%
compared with enalapril [24, 25].
Ivabradine reduces the heart rate by specifically inhibiting
the cardiac sinus node pacing current. The SHIFT study
showed that ivabradine reduces the relative risk of cardiovas-
cular death and hospitalization by 18% and significantly im-
proves left ventricular function and life quality of patients
with HF [26, 27]. Digitalis drugs produce positive inotropic
effects by inhibiting Na+/K+-ATPases, enhance the parasym-
pathetic activity, and reduce atrioventricular conduction.
Studies have shown that [28] a meta-analysis showed that the
long-term use of digoxin by patients with heart failure has a
neutral effect on mortality, but reduces the hospitalization risk
[29]. Nitrates can also be used by patients with uncontrolled
angina. Trimetazidine facilitates the improvement of the Left
Ventricular Ejection Fraction (LVEF) [30, 31].
Currently, percutaneous cardiovascular interventions and
coronary artery bypass grafting are applied to restore vascu-
larization [32]. Prophylactic implantable cardioverter defi-
brillators reduce the rate of sudden arrhythmic death in pa-
tients with HFrEF, which is more important for IHF because
of a higher risk of malignant arrhythmia compared with
non-IHF [33]. CRT can be used for HF patients with cardiac
dyssynchrony; however, not all patients respond to CRT,
and it appears that patients with non-ischemic etiology have
a greater increase in the LVEF and a decrease in the NYHA
functional class after CRT than patients with ischemic heart
disease [34]. Mechanical Circulatory Support (MCS) sys-
tems, particularly extracorporeal life support and extracor-
poreal membrane oxygenation, can be used as a ‘bridge to
decision’ for patients with acute and rapidly deteriorating
HF or cardiogenic shock to stabilize hemodynamics, recover
end-organ functions, and allow for a full clinical evaluation
for the possibility of either heart transplantation or a more
durable MCS device [35, 36]. For patients with severe end-
stage heart failure, heart transplantation is the only treatment
[37, 38].
In the past 30 years, there has been significant progress in
the treatment of heart failure. However, the prognosis of pa-
tients with heart failure is still unsatisfactory. In the ESC-HF
pilot study, hospitalized heart failure patients and stable/out-
of-bed patients had 12-month all-cause mortality rates of 17%
610 Current Stem Cell Research & Therapy, 2021, Vol. 16, No. 5 Liang et al.

Fig. (1). Schematic illustration of the pathogenesis of cardiomyocyte death in heart failure. When cardiomyocytes are challenged by hypoxic
and nutrient deprivation conditions such as myocardial infarction, endothelial and inflammatory cells produce a series of inflammatory cyto-
kines and miRNAs. Uptake of miRNAs into cardiomyocytes induces an increase of proapoptotic gene expression and decreases ant-apoptotic
gene expression through regulation of target genes. Dysregulation of genes such as STAT3 in cardiomyocytes reduces cell survival, increases
reactive oxygen species production, and impairs autophagy. Together with inflammatory attack, cardiomyocytes undergo apoptosis. Fibro-
blasts transition to myofibroblasts that activate in the infarction border area. TGF-β signaling in the activated myofibroblasts drives fibrosis
and scar formation. Ultimately, loss of cardiomyocytes reduces cardiac functions, leading to hypertrophy and heart failure. (A higher resolu-
tion / colour version of this figure is available in the electronic copy of the article).

and 7%, respectively, and 12-month hospitalization rates of
44% and 32%, respectively [39]. The 5-year survival rate of
patients with heart failure is still less than 50%. The treat-
ments for IHF still require further exploration. Considering
that stem cells can be differentiated into functional cardio-
myocytes or improve cardiomyocyte survival by paracrine
functions, stem cell therapy may have certain application
prospects for the treatment of ischemic HF.
4. MESENCHYMAL STEM CELLS
Mesenchymal Stem Cells (MSCs) (also referred to as
mesenchymal or multipotent stromal cells) were first dis-
covered in bone marrow in the early 1970s [40]. MSCs are
multipotent stem cells that can be isolated from various
adult tissues such as bone marrow, umbilical cord, adipose,
peripheral blood, liver, and tooth roots [41]. The criteria for
MSC identification were traced back to a decade ago by the
International Committee for Cell Therapy (ISCT). Cur-
rently, the ISCT recommends to the term “multipotent mes-
enchymal stromal cells” (MSCs) instead of “mesenchymal
stem cells”. However, researchers are more prone to use
“mesenchymal stromal cells” or “mesenchymal stem cells”.
4.1. Tissue Sources of MSCs
4.1.1. Bone Marrow-derived MSCs
BM-MSCs are isolated from BM cells by Percoll-based
density gradient centrifugation [42]. After seeding, MSCs
are adherent cells and aggregate into uniform cell colonies
to form fibroblast-like clones. Under a phase-contrast mi-
croscope, the dominant cells have a spindle or whirlpool-
like shape with ample cytoplasm and a large dark nucleolus.
MSCs undergo rapid proliferation after 7 days of cultivation
and can reach 80%-90% confluence by day 14.
4.1.2. Placenta-derived MSCs
MSCs have been identified in the placenta [43]. There
are two methods of MSC isolation from the placenta. The
placenta is first mashed into small pieces and digested by
trypsin, DNase, and collagenase. To promote MSC adhe-
sion, digested cells are blocked with external placenta tis-
sues before seeding [44].
4.1.3. Umbilical Cord Blood-derived MSCs (UB-MSCs)
In 2000, Erices et al., isolated mononuclear cells from
the umbilical cord blood of preterm infants and found that
25% of the cell population gave rise to fibroblast-like cells
and expressed MSC-related surface markers [45]. Cell cycle
analysis revealed that >85% of these cells were in the
G0/G1 phase, suggesting a strong proliferative potential.
UM-MSCs can also be obtained by Percoll-based gradient
density centrifugation.
4.1.4. Adipose Tissue-derived MSCs (AT-MSCs)
MSCs were first identified in adipose tissue suspensions
obtained by liposuction in 2001 [46]. After culture, these
MSC Therapy for Ischemic Heart Failure Patients
cells display prompt proliferation and multilineage differen-
tiation [47, 48]. After digestion by trypsin, MSCs in adipose
tissues can be isolated by Percoll-based density gradient
centrifugation similarly to BM-MSCs.
4.2. Biological Properties of MSCs
Multilineage differentiation, immunomodulation, and
anti-inflammatory effects are the main properties of MSCs.
When cultivated MSCs are stimulated by certain cytokines,
they give rise to osteoblasts [49], chondrocytes [50], adipo-
cytes [51], skeletal muscle cells [52], neurons [53], cardio-
myocytes [54], and endothelial cells [55]. MSCs have sev-
eral advantages for cell therapy, including low immuno-
genicity, immunoregulation, and anti-inflammatory effects.
Studies have shown that MSCs do not express major histo-
compatibility complex (MHC)-II molecules, cell membrane
surface glycoprotein (Fas) ligands, or costimulatory mole-
cules (B7-1, B7-2, CD40, and CD40L), and the expression
of MHC-I molecules is low [56]. When MSCs are cocul-
tured with a mixed population of T cells or with mitogen-
stimulated T cells, T cell proliferation is reduced signifi-
cantly, implying low immunogenicity of MSCs [57].
4.3. Characteristics of MSCs Isolated from Different
Tissues
The common surface markers of MSCs in different tis-
sues are CD29, CD13, CD44, and CD10 [58]. Nonetheless,
MSCs isolated from different tissues also express their dis-
tinct markers, as listed in Table 1 [59-62]. Apart from sur-
face markers, MSCs from different tissues have different
capacities for lineage differentiation. When BM-, cold blood-,
adipose tissue-, and placenta-derived MSCs are cultivated in
vitro, BM-MSCs have a longer doubling time than other
MSC types [63]. Upon passaging, placenta-derived MSCs
can be subcultured more than the other MSC types [63].
When the same number of MSCs are seeded in CFU assays,
BM- and cord blood-MSCs give rise to more colonies than
Table 1. Comparison of MSCs isolated from various origins.
- Bone Marrow
Surface markers SH2, SH3, CD71,
CD90, CD106,
CD120a, CD124 [59]
Proliferation capacity in vitro - -
Number of passages in vitroA [63] + +
B
Self-renewal + +
C
Tri-lineage differentiation potential ++
[63]
Suppression of T proliferation in ++
vitro [63]
Suppression of B cell activation ++
Note:
A, Number of passages before reaching cell replicative senescence.
B, Self-renewal of MSCs is the number of MSCs colonies after seeding in a CFU-F assay.
C, Trilineage differentiation includes adipocytes, osteoblasts, and chondrocytes.
Current Stem Cell Research & Therapy, 2021, Vol. 16, No. 5 611
the other MSC types, suggesting that they have a stronger
self-renewal property [63]. Upon differentiation, BM- and
AT-MSCs display dramatic differentiation potentials to gen-
erate osteoblasts, adipocytes, and chondrocytes, whereas
cord blood- and placenta-derived MSCs show weak differ-
entiation potential [63]. Moreover, adipocytes differentiated
from AT-MSCs secrete high amounts of collagen type II
and III, whereas adipocytes derived from BM-MSCs pro-
duce high amounts of angiogenic factors such as TGF-β1,
TGF-β2, collagen type II and IV, heparan sulfate, laminin,
and aggrecan [64, 65].
Modulation of immune and inflammatory responses is
also an important feature of MSCs. When MSCs are cocul-
tured with mononuclear cells isolated from human periph-
eral blood, BM-MSCs produce higher amounts of IL-10 and
TGF-β1, and potently suppress T cell proliferation induced
by phytohemagglutinin compared with MSCs from other
sources [63]. MSCs inhibit the inflammatory cascade via
several mechanisms, most of which are mediated by anti-
inflammatory cytokines and factors released from MSCs.
Lipopolysaccharide and TNF-α activate NF-kB signaling in
macrophages, leading to inflammatory cytokine production
and the recruitment of neutrophils to enhance the inflamma-
tion cascade. Paradoxically, activation of NF-kB signaling
by lipopolysaccharide and TNF-α induces TNF-α-stimulated
gene/protein 6 (TSG-6) and Prostaglandin E2 (PGE2) ex-
pression [66, 67]. Once secreted, TSG-6 binds to CD44
hyaluronan that prohibits nuclear factor-κB (NF-κB) activa-
tion in macrophages and PGE2 stimulates switching macro-
phage polarization from the proinflammatory M1 phenotype
to the anti-inflammatory M2 phenotype [66, 67]. As intro-
duced earlier, activation of NF-kB signaling is crucial for
cardiomyocyte death in myocardial infarction. Therefore,
MSCs have therapeutic properties to prevent cardiomyo-
cytes from ischemic injury.
Next, we focus on the differentiation potential of MSCs
for cardiomyocytes and paracrine functions of MSCs, both
Umbilical Blood Adipose Tissue Placenta
CD13, CD44, CD49e, CD9, CD13, CD54, CD166, SH-2/CD105, SH-
CD54, CD90, ASMA, SH2, CD55, CD71, CD90, 3, SH-4, SSEA-4, TRA-1-
SH3, HLA-ABC [60] CD105, CD146 [61] 61, TRA-1-80 [62]
- -
+ ++
+ +
- ++ +
+ ++ +
+ ++ +
612 Current Stem Cell Research & Therapy, 2021, Vol. 16, No. 5
of which are implicated substantially in the treatment of
heart failure.
5. MSCS AND CARDIOMYOCYTES
5.1. In Vitro
With regard to MSC differentiation into cardiomyocytes,
early studies showed that specific microenvironmental con-
ditions, such as 5-azacytidine and platelet-derived growth
factor β treatments, promote MSC differentiation into car-
diomyocytes. These myocytes maintain some features of
cardiomyocytes, such as the expression of β-myosin heavy
chain and spontaneous calcium fluxes [68, 69]. However, in
another study, rat BM-MSCs could neither be expanded
extensively in vitro nor induced to differentiate in an ex-
pected cardiomyogenic manner by 5-azacytidine-treatment
[70]. In parallel, Alvarez-Dolado et al., reported that BM-
MSCs fuse with cells within the heart to form mature car-
diomyocytes rather than trans-differentiate [71].
Indeed, the regulatory mechanisms underlying the multi-
lineage differentiation of MSCs are very complicated. None-
theless, accumulating evidence has shown that activation or
inhibition of certain transcription factors direct MSC differen-
tiation toward definite lineage specification. For example,
Pax3 is a member of the paired box family. Exogenous over-
expression of Pax3 in MSCs restrains their differentiation
toward myogenic cells compared with other lineages [72]. By
exogenous overexpression and knockdown of candidate gene
expression, some key transcription factors that specifically
educate MSC differentiation to ANP and cTnI-expressing
cardiomyocytes have been identified. These transcription
factors are GATA4, Nkx2.5, myocardin, thioredoxin-1, and
Notch1 [73, 74]. Pretreatment with Transforming Growth
Factor-beta 1(TGF-β1) enhances the differentiation of rat
BM-MSCs toward the cardiomyogenic phenotype and im-
proves cardiac functions in rats with heart failure [75]. Proto-
cols are being optimized for stable and efficient cardiomyo-
cyte production from MSCs. For example, the addition of 5-
Aza, BMP-2, and DMSO induces MSC differentiation into
cardiomyocyte-like cells within 24 hours. Furthermore, 2
weeks of coincubation of myocardial cell broth results in car-
diomyocyte production from MSCs [76].
5.2. In Vivo
In line with the in vitro studies, the expression of car-
diomyocyte markers in labelled MSCs has been detected by
immunofluorescence at 14 days after MSC transplantation
in swine models of myocardial infarction [77, 78]. When
MSCs were engineered to express thioredoxin-1 and in-
jected into the peri-infarct area of rats with left anterior de-
scending coronary artery ligation, increases in cardiac func-
tions and the capillary density were observed by echocardi-
ography, and fibrosis was reduced compared with control
groups [79]. However, engrafted MSCs can not differentiate
to cardiomyocytes in dogs and sheep models of myocardial
infarction [80, 81]. Therefore, whether MSCs can differenti-
ate into cardiomyocytes is yet to be confirmed.
There are several challenges when evaluating the MSC
differentiation potential in vivo. First, upon transplantation,
MSCs survive for only a few weeks [82]. When BM-MSCs
Liang et al.
were injected into the border zone of myocardial infarction
in rats, the percentage of BM-MSCs in the heart decreased
rapidly from 34%-80% to 0.3%-3.5% in 6 weeks, which
was independent of the cell number and application time
[83]. Second MSC homing is one of the critical issues in
cell therapy. When tracing by the nuclear affinity labeling
technique, only a few percent of the injected MSCs re-
mained in the heart at 2 weeks after intramuscular or intra-
coronary administration of MSCs [84]. Third, it is difficult
to assess the functionality of cardiomyocytes differentiated
from MSCs in vivo.
6. EXOSOMES DERIVED FROM MSCs
6.1. Brief Characterization
When immunodeficient mice were subjected to acute
myocardial infarction and then injected with human MSCs
via the tail vein, cardiac functions improved significantly in
the hMSC-treated group compared with controls [85, 86].
Nevertheless, hMSCs could not be detected in the heart by
immunohistochemistry of GFR, real-time PCR of human
Alu sequences, or traditional PCR of human-specific mito-
chondrial cytochrome oxidase I. Instead, microarray assays
and ELISAs have revealed the production of multiple pro-
tective factors from hMSCs in vitro before transplantation.
When supernatants of cultivated hMSCs were added to hy-
poxic HL-1 cardiomyocytes and Human Umbilical Vein
Endothelial Cells (HUVECs), apoptosis was reduced sig-
nificantly compared with the control condition.
Indeed, similarly to other mesenchymal cells, MSCs se-
crete many exosomes to regulate local and distant cell com-
munication. Exosomes are a type of extracellular vesicle with
a diameter between 30 and 150 nm. They form by fusion of
late endosomes/multivesicular bodies in the plasma mem-
brane and contain proteins, RNAs, lipids, and metabolites.
Once released, exosomes transfer molecules from MSCs to
other cells via membrane vesicle trafficking for cell-to-cell
communication, thereby regulating the immune response,
inflammation, and angiogenesis. Exosomes have a series of
surface markers for recognition such as CD9, CD63, and
CD81 [87]. Presently, 850 gene products and 150 miRNAs
have been found in exosomes secreted from MSCs.
6.2. Exosome Isolation
Considering that the density of exosomes ranges from
1.10 to 1.21 g/mL in sucrose, exosomes can be isolated by
density-gradient-based ultracentrifugation [88]. Exosomes
can also be isolated by size-exclusion chromatography [89].
Overall, the isolation of exosomes is time-consuming and
expensive. Recently, polyester capillary-channeled polymer
fibers in hydrophobic interaction chromatography have been
used to isolate exosomes from human urine samples. The
yield was high and productive when assessed by scanning
electron microscopy [90]. To obtain a higher yield of
exosomes from biological fluids, tangential flow filtration
has been tested, which reduced the isolation time and
recovers a reproducible number of exosomes among batches
[91]. These methods have optimized efficient exosome iso-
lation with high quality. After isolation, the yielded
exosomes are characterized by transmission electron mi-
croscopy or the Zetasizer Nano range for size and number.
MSC Therapy for Ischemic Heart Failure Patients
The biomarker expression can also be examined by western
blotting and flow cytometry.
6.3. Distinct Properties of Exosomes from MSC Types
The phenotype and characteristics of exosomes vary ac-
cording to the origin of MSCs. Baglio et al. compared the
tRNA profiles of exosomes from BM- and adipose-derived
MSCs and found that exosomes secreted from BM-MSCs
had higher levels of Nanog, POU5F1A/B, and Sox2 [92]. In
another study, Wang et al., compared the therapeutic effects
of MSCs from the endometrium, BM, and adipose tissue in
a rat model of myocardial infarction. They found that
exosomes from endometrial MSCs carried miR-21, whereas
exosomes from BM-MSCs and adipose-derived MSCs did
not. The blockade of miR-21 by anti-miR treatment abro-
gated the anti-apoptotic and angiogenic effects of EnMSCs.
Accordingly, endometrial MSC engraftment resulted in
greater protection of cardiomyocyte survival and angiogene-
sis [93].
Despite the fact that the properties of exosomes depend
on the origin of MSCs, they are the executer of MSC func-
tions. When added to the cell culture medium, exosomes
promote cell proliferation and migration of endothelial cells
[94], epithelial cells [95], and fibroblasts [96]. When cul-
tured with T cells in vitro, exosomes from MSCs inhibit T
cell differentiation and activation as well as IFN-γ release
[97]. When added to the HUVEC culture medium,
exosomes from MSCs promote cell proliferation and migra-
tion [94], angiogenic factor production, and tubular forma-
tion [98, 99].
6.4. Exosomes and Cardiomyocytes
Because MSCs improve cardiomyocyte survival and
functions via their secreted exosomes, transfection of a gene
of interest into MSCs has become a technique to obtain
exosomes for therapeutic purposes. Exosomes from atorvas-
tatin-pretreated MSCs contain higher amounts of long non-
coding RNA H19 than untreated MSCs. When delivered,
long non-coding RNA H19 promotes endothelial cell and
cardiomyocyte survival under hypoxia in vitro. When in-
jected into a rat model of myocardial infarction, long non-
coding RNA H19 increases VEGF and ICAM-1 expression
in endothelial cells and decreases IL-6 and TNF-α levels in
the peri-infarct area [100]. Tissue matrix metalloproteinase
inhibitor 2 inhibits metalloproteinases that assist cardiac
remodeling. After BM-MSCs were transfected with TIMP2,
exosomes from the culture medium were injected into the
peri-infarct zone immediately after coronary artery ligation
in rats. Thirty days after injection, improved cardiac func-
tions were observed by echocardiography. TIMP2-
containing exosomes promote cardiomyocyte survival via
activation of the Akt/frizzled-related protein 2 (Sfrp2) path-
way [101]. Exosomes secreted from MSCs contain various
factors, including HGF and PGF, to assist MSC differentia-
tion into cardiomyocytes [102].
MicroRNAs (miRNAs) are important gene expression
regulators enriched in exosomes. MiR-24 [103], miR-214
[103], mR-301 [104], miR-125b [105], miR-132 [106],
miR-21a-5p [107], miR-590-3p [108], miR-133 [109], miR-
210 [110], and miR-21 [93] have been reported to suppress
Current Stem Cell Research & Therapy, 2021, Vol. 16, No. 5 613
apoptotic protein expression, increase anti-apoptotic protein
expression, improve angiogenic gene expression, and ame-
liorate oxidative stress, leading to enhanced cardiomyocyte
survival and functions in various models of MI. For thera-
peutic purposes, preconditioned MSCs and transfection of
miRNA constructs into MSCs are used to obtain miRNAs.
Similar to MSCs, exosomes from MSCs are well tolerated
upon injection. When exosomes isolated from human MSCs
are injected into mice with oxygen-induced retinopathy, in-
travitreal exosome administration increases vascular flow and
reverts retinal thinning without any immunogenicity effects
[111]. A clinical study (NCT03384433) started last year to
evaluate the effect of miR-124-containing exosomes in pa-
tients with acute ischemic stroke. MSC exosomes that im-
prove cardiomyocyte fate after MI are listed in Table 2 [100,
101, 103-107, 109, 93, 112-119 114-121].
Taken together, although the paracrine mechanism is
complex and not completely understood, the use of MSC-
derived paracrine factors may be a therapeutic strategy for
myocardial recovery. Certain paracrine factors in MSC-
derived exosomes may be beneficial to repair myocardial
injury with high efficacy.
6.5. Clinical Trials of MSC Treatments for Patients with
Heart Failure
Human MSCs are currently applied to the treatment of
myocardial infarction, autoimmune diseases (multiple scle-
rosis, rheumatoid arthritis, and Crohn’s disease), graft-
versus-host disease, wound repair, ischemia/stroke, and liver
diseases, and to hematopoietic stem cell engraftment [120].
Expanded MSCs for clinical applications are classified as an
advanced therapy medicinal product according to the Euro-
pean Medicines Agency regulation number 1394/2007 of
the European Commission [121, 122].
In 2009, a randomized, double-blinded, placebo-
controlled trial was performed, in which patients with AMI
were injected with bone marrow MSCs. Bone marrow MSC
treatment increased the LVEF and reversed remodeling in
post-infarction patients [123]. In another randomized trial,
allogeneic and autologous bone marrow MSCs were admin-
istered to 30 patients with ischemic cardiomyopathy, who
were followed up for 13 months. Compared with the pla-
cebo, autologous MSC therapy improved the 6-minute walk
test and Minnesota living with heart failure questionnaire
but did not improve exercise VO2 max. Allogeneic and
autologous MSCs reduced the mean infarct size by -33.21%
(95% CI, -43.61% to -22.81%; P <0.001) and sphericity
index, but did not increase the LVEF [124]. In the TAC-
HFT trial, 65 patients with ischemic cardiomyopathy and an
LVEF of <50% received bone marrow MSCs, bone marrow-
derived mononuclear cells, or a placebo. The 1-year inci-
dence of serious adverse events was similar between bone
marrow MSC, bone marrow MSC, and placebo treatments.
Nonetheless, the Minnesota Living With Heart Failure score
showed improved cardiac functions after treatment with
MSCs (-6.3; 95% CI, -15.0 to 2.4; repeated measures of
variance, P=0.02) and bone marrow mononuclear cells
(-8.2; 95% CI, -17.4 to 0.97; P=0.005), but not with the pla-
cebo (0.4; 95% CI, -9.45 to 10.25; P=0.38). The 6-minute
walk distance and infarct size as a percentage of the LV
614 Current Stem Cell Research & Therapy, 2021, Vol. 16, No. 5 Liang et al.

Table 2. Summary of mesenchymal stem cell-derived exosomes for the treatment of myocardial infarction.

Exosome Component Origin Property References

Proteins and factors

CXCR4 BM Anti-apoptotic, increased angiogenesis [112]

GATA4 BM Anti-apoptotic, increased angiogenesis [113, 114]

SDF-1 Umbilical cord-MSC Increased angiogenesis and inhibited autophagy [115]

RNAs

miR-24 BM Anti-apoptotic [116]

miR-214 ADSC Anti-apoptotic [80]

TIMP2 Umbilical cord-MSC Anti-apoptotic [101]

Long non-coding H19 BM Anti-apoptosis [100]

miR-301 BM Inhibited autophagy [104]

miR-125b BM Anti-apoptotic, improved autophagy [117, 105]

miR-132 BM Anti-apoptotic [106]

miR-21a-5p BM Anti-apoptototic [107]

miR-133 BM Anti-apoptototic [109]

miR-210 BM Anti-apoptotic, increased angiogenesis [108]

miR-21 Human endometrium Anti-apoptotic, increased angiogenesis [93]

miR-22 BM Anti-apoptotic [119]

mass were improved by BM-MSCs only. The left ventricu-
lar chamber volume and LVEF did not significantly change
in within group or between-group comparisons [125].
In the TRIDENT study, 30 patients with ischemic car-
diomyopathy received 20 million (n=15) or 100 million al-
logeneic bone marrow MSCs (n=15) via transendocardial
injection [126]. Patients who received 100 million BM-
MSCs had a reduced infarcted size and increased cardiac
functions [126]. In the C-CURE multicenter randomized
trial, LVEF was 1.3-fold higher and the left ventricular end-
systolic volume was reduced by 65% in IHF patients who
received bone marrow MSCs compared with those on the
standard of care alone. The 6-minute walk distance was also
improved by bone marrow MSCs (+62 ± 18 m vs. -15 ± 20
m, p < 0.01) [137]. In ischemic heart failure patients with
severe cardiac dysfunction (LVEF<45%), MSC treatment
significantly improved the LVEF by 6.2% compared with
the placebo [128].
In addition to bone marrow MSCs, other MSC types
have been tested in IHF patients. After receiving autologous
cardiopoietic MSCs, IHF patients showed a progressive
decrease in both LVEDV and LVESV within 52 weeks after
treatment. However, other measurements, including the
LVEF, 6-min walk distance, and Minnesota Living with
Heart Failure Questionnaire, did not change [129]. Com-
pared with bone marrow MSCs, umbilical cord-derived
MSC-treated patients also exhibited significant improve-
ments in the LVEF, NYHA class, and Minnesota Living
with heart failure questionnaire [130]. Table 3 lists the re-
sults of clinical trials of MSCs in patients with MI or
ischemic cardiomyopathy [123-135].
Bone marrow mononuclear cells, CD34+ cells, and car-
diac progenitor cells have been tested in patients with heart
failure, and their therapeutic effects on cardiac functions are
listed in Table 3. Overall, there are limited clinical studies on
bone marrow MSCs with small sample sizes of AMI and IHF
patients and relatively short follow-up durations. MSC dos-
ages and administration routes vary among trials. However,
most clinical trials suggest that bone marrow MSCs increase
the LVEF, reduce the infarct size, and improve other clinical
measurements such as the 6-min walk distance.
7. PERSPECTIVES
MSC treatment has been shown to improve the cardio-
myocyte number and functions in animal models of MI and
patients with MI or ischemic cardiomyopathy. A short per-
sistence of MSCs after injection has been noted in vivo,
which is independent of the administration route. Alterna-
tively, MSC-derived exosomes have several therapeutic
advantages: (1) genetic features of exosomes can be
achieved by manipulation of MSCs by gene/miRNA trans-
fer; (2) because of their small size, exosomes can taken up
efficiency by cells after injection; (3) exosomes can be mass
produced for clinical practice; (4) exosomes can be repeat-
edly applied to treat patients with lower costs and better
efficacy compared with MSCs.
MSC Therapy for Ischemic Heart Failure Patients Current Stem Cell Research & Therapy, 2021, Vol. 16, No. 5 615

Table 3. Summary of MSC treatments in randomized clinical trials of myocardial infarction and ischemic cardiomyopathy.

First Author, Pub- Patients’ Cell Dose Follow

lication Year & Characteris- Design Number Origin (Million) / Admi- Up Main Findings
Reference tics (LVEF) nistration Route (years)

MSCs -

AMI, LVEF
averaged
Increased LVEF, improved
Hare JM, 2009, 48.7% for
DB, PC 53 BM 0.5, 1.6, and 5/kg/IV 0.5 forced expiratory volume and
[123] placebo and
global symptom score
50.4% for
MSCs group

Hare JM, 2012 LVEF no change; improved 6-

ICM, Randomized,
30 BM 20, 100, 200/TEN 1.1 minute walk test; reduced
[124] LVEF<50% no PC
LVEDV and infarct size

LVEF no change; improved

Heldman AW, 2014 ICM,
DB, PC 65 BM 200/TEN 0.08 functional capacity, infarct size
[125] LVEF<50%
and 6-min walk distance

Florea V, 2017 Increased LVEF, reduced scar

ICM,
DB, no PC 30 BM 100, 20/TEN 1 size and improved NYHA class
[126] LVEF≤50%
improved in high dose

Increased LVEF; improved 6-

Bartunek J, 2013 LVEF: 15%- Prospective,
36 BM 733/TEN 2 min walk test, LVESV and
[127] 40% DB, PC
NYHA class

Increased LVEF; reduced

ICM, LVEF
Mathiasen AB, 2015 LVESV reduced, stroke volume
<45%, DB, PC 59 BM (77.5+67.9)/TEN 0.5
[128] improved, and myocardial mass
NYHA II-III
improved

Bartunek J, 2017 ICM, LVEF no change; decreased

DB, PC 348 cardiopoietic 600/TEN 0.7
[129] LVEF≤35% LVEDV and LVESV

Increased LVEF; improved

ICM and
Bartolucci J, 2017 Umbilical NYHA class and Minnesota
NICM, DB, PC 30 1/kg/IV 1
[130] cord Living with Heart Failure
LVEF≤40%
Questionnaire

Jeans K, 2017 Chonic IHF, Single-

Adipose
LVEF center phase 10 110 million/TEN 0.5 Increased LVEF
[136] MSC

45% 1 study

LVEF≤40% MSCs alone

alleviate LV dysfunction, alle-
Roberto Bolli, 2018 with HF of Randomized, 150/IV,CPCs alone
162 BM 1 viate LV dysfunction and re-
[137] ischemic DB, PC 5/IV,MSCs + CPCs
modeling
etiology 150+5/IV

Karantalis V, 2014 ICM, LVEF prospective, Increased LVEF; decreased

6 BM Not reported/TEP 1.5
[131] not reported no PC scar mass

Increased LVEF; improved

Guijarro D, 2016 ICM,
prospective 10 BM 61.5/TEN 0.08 LVEDV, 6-min walk test and
[132] LVEF≤35%
NYHA class

improvements in exercise time,

Stable coro-
Mathiasen AB, 2013 open, non- angina class (CCS), weekly
nary artery 31 BM 21.5/TEN 3
[133] randomized number of angina attacks and
disease
use of nitroglycerine

Table 3 contd….
616 Current Stem Cell Research & Therapy, 2021, Vol. 16, No. 5 Liang et al.

First Author, Publi- Patients’ Cell Dose (Mil- Follow

cation Year & Ref- Characteris- Design Number Origin lion)/Administratio up Main Findings
erence tics (LVEF) n Route (years)

Viswanathan C, 2010 MI, LVEF (5.86 ± 2.36)/TEP LVEF no change; improved

PC 15 BM 0.5
[134] not reported mean percentage perfusion

Wang JA, 2006 Dilated CM, Prospective, LVEF no change; improved

12 BM 2/IC 0.5 BNP level and 6-min walk
[135] LVEF<45% PC distance

Other types of stem

-
cells

Boris A, 2014 BM, LVEF and 6-minute walk test

IHF, LVEF Randomized, 20 injections per
60 0.5 no change; scar size and re-
[138] <35% DB, PC CD133+BMC 0.5ml/TEP
gional perfusion improved

Ischemic Phase 1,
Atul R, 2012 cardiomyopa- randomized, 1X106/5X105/ Increased LVEF, decreased
33 CPC 1
[139] thy with open-label IC infarct size
LVEF≤40% trail

Helena Martino,
2015 LVEF<35% Randomized, BM mononu- No change of LVEF, diastolic
160 236/IV 1
with NIDCM DB, PC clear cells volumes and ejection fraction
[140]

Stephen Hamshere, Random-

2015 LVEF ≤ 45%
ized，DB, 60 BM 216/IV 1 Increased LVEF
with DCM
[141] PC

Christina Paitazoglou,
LVEF <45%
2019 DB, PC 138 BM 100/IV 0.5 Increased LVEF
with IHF
[142]

Abbreviations: CM, Cardiomyopathy; ICM: Ischemic Cardiomyopathy, DCM: Dilated Cardiomyopathy, NIDCM: Non-Ischemic Dilated Cardiomyopathy; AMI: Acute Myocardial
Infarction, SB: Single-Blinded, DB: Double-Blinded, PC: Placebo-Controlled, BM-MSCs: Bone Marrow Mesenchymal Stem Cells, CPCs: Cardiac Progenitor Cells; IV: Intrave-
nous, ICM: Ischemic Cardiomyopathy, ICM: Ischemic Cardiomyopathy, DCM: Dilated Cardiomyopathy, NIDCM: Non-Ischemic Dilated Cardiomyopathy, IC: Intracoronary, TEN:
Trans-endocardial, TEP: Trans-Epicardial, LVEF: Left Ventricular Ejection Fraction, LVEDV: Left Ventricular End-Diastolic Volumes, LVESV: Left Ventricular End-Systolic
Volumes, AR: Arrhythmogenicity, BNP: B-type Natriuretic Peptide.

Recently, Yang et al., synthesized Poly-(Glycerol Se- cial for the treatment of myocardial ischemic injury and
bacate) (PGS) and Poly-(ε-Caprolactone) (PCL) scaffolds ischemic heart failure. Among all types of stem cells, the use
by 3D-printing technology and implanted the scaffolds of MSCs and exosomes from MSCs has become a promising
epicardially into a rat model of myocardial infarction [143]. therapeutic strategy to reduce the infarct area and improve the
Four weeks after scaffold implantation, the LVEF improved ejection fraction in patients with ischemic heart failure.
and the infarct size decreased significantly in the PGS-PCL
group compared with the control. Histological analysis CONSENT FOR PUBLICATION
showed that the 3D-printed PGS-PCL scaffold promoted
vascularization and tissue repair, and inhibited myocardial Not applicable.
apoptosis. Maiullari et al., integrated the use of 3D bioprint-
ing with induced stem cell-derived cardiomyocytes and FUNDING
HUVECs encapsulated in hydrogel [144]. These advances None.
in bioprinting technology may improve the efficacy of cell-
and exosome-based therapies for treating patients with MI
CONFLICT OF INTEREST
and ischemic cardiomyopathy.
The authors declare no conflict of interest, financial or
CONCLUSION otherwise.
Although great progress has been made to treat ischemic
ACKNOWLEDGEMENTS
heart disease, the 5-year mortality rate of heart failure is still
as high as 50%, which is becoming a major health problem We thank Mitchell Arico from Liwen Bianji, Edanz
worldwide. Reducing post-ischemic myocardial injury and Group China (www.liwenbianji.cn/ac), for editing the Eng-
promoting cardiomyocyte and vascular regeneration are cru- lish language of this manuscript.
MSC Therapy for Ischemic Heart Failure Patients
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