Archives of Medical Research 48 (2017) 133e146

REVIEW ARTICLE
Mesenchymal Stem Cell-based Therapy as a New Horizon for Kidney Injuries
Amaneh Mohammadi Roushandeh,a Marzie Bahadori,b and Mehryar Habibi Roudkenarc
a
Anatomical Sciences Department, Medicine Faculty, Hamadan University of Medical Sciences, Hamadan, Iran
b
Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
c
Medical Biotechnology Research Center, Paramedicine Faculty, Guilan University of Medical Sciences Rasht, Iran
Received for publication August 29, 2016; accepted February 9, 2017 (ARCMED-D-16-00514).

Today, the prevalence of kidney diseases is increasing around the world, but there has still
been no effective medical treatment. The therapeutic choices are confined to supportive
cares and preventive strategies. Currently, mesenchymal stem cells (MSCs)-based cell
therapy was proposed for the treatment of kidney injuries. However, after the transplan-
tation of MSCs, they are exposed to masses of cytotoxic factors involving an inflamma-
tory cytokine storm, a nutritionally-poor hypoxic environment and oxidative stresses that
finally lead to minimize the efficacy of MSCs based cell therapy. Therefore, several inno-
vative strategies were developed in order to potentiate MSCs to withstand the unfavorable
microenvironments of the injured kidney tissues and improve their therapeutic potentials.
This review aims to introduce MSCs as a new modality in the treatment of renal failure.
Here, we discuss the clinical trials of MSCs-based therapy in kidney diseases as well as
the in vivo studies dealing with MSCs application in kidney injuries mainly from the pro-
liferation, differentiation, migration and survival points of view. The obstacles and chal-
lenges of this new modality in kidney injuries are also discussed. Ó 2017 IMSS.
Published by Elsevier Inc.
Key Words: Renal failure, AKI, MSCs, Cell therapy, Clinical trial.

Introduction and relieve the patients from anemia and other symptoms
of kidney failure such as bone defects and fatigue (10,11).
Acute kidney injury (AKI), an abrupt deficiency in renal
Although the aforementioned therapies increased the
filtration function, has high prevalence and is increasing
survival rate of patients suffering from renal failure, it
annually about 8%. Chronic renal failure has the prevalence
was not satisfactory, and the morbidity and mortality
about 8 to 16% and is a significant clinical problem (1e4).
rates are still high. On the other hand, the expenses of
Currently, three main strategies are applied for the treat-
hemodialysis are high and its side complications such as
ment of renal failure. Hemodialysis is the most common
hypotension, infection, gastrointestinal bleeding and psy-
method used to treat both advanced and permanent kidney
chological problems threaten the patients. Accessibility to
failures (5e7). Kidney transplantation is another strategy
a compatible kidney organ is another challenge. Of note,
in which a healthy kidney from a compatible donor is trans-
the number of patients who need kidney transplantation is
planted to a recipient patient (8,9). The last strategy for the
more than those of organ donors. Hence, some patients
treatment of renal failure is symptom-based treatment. The
have to be in the waiting list, and even may die before
patients neither undergo hemodialysis nor kidney transplan-
receiving the organ. In addition, the effects of conservative
tation, but they receive Pharmacological and dietary regi-
therapy (symptom-based therapy) need more attention and
mens. These treatment strategies alleviate the symptoms
should be carefully examined in older patients (12e14).
Therefore, establishment of a novel treatment is highly
Address reprint requests to: Mehryar Habibi Roudkenar, Medical important in order to improve the life quality of patients
Biotechnology Research Center, Paramedicine Faculty, Guilan University suffering from renal failure, decrease the morbidity and mor-
of Medical Sciences Rasht, Tehran, Islamic Republic of Iran; Phone: tality rates, address the problems of hemodialysis and organ
(þ98) 9126944566; FAX: þ98-31-42565051; E-mail: roudkenar@gums.
ac.ir.
transplantation, and decrease the cost of treatment (14).

0188-4409/$ - see front matter. Copyright Ó 2017 IMSS. Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.arcmed.2017.03.007
134 Roushandeh et al./ Archives of Medical Research 48 (2017) 133e146
Mesenchymal stem cell (MSC)-based cell therapy is an
innovative approach in tissue regeneration that has a poten-
tial capability in the treatment of renal failure. Currently,
dozens of studies were designed in the fields of stem cells
with different sources, preconditioning modalities, and
routes of injection combined with a variety of pharmaco-
logical agents and doses of in vitro application in preclini-
cal and clinical studies (2,14e21).
MSCs are type of multipotent stem cells isolated from
different tissues such as bone marrow, adipose tissue, cord
blood, amniotic membrane, human glomeruli, human
saphenous vein, human periosteum and human synovial
fluid (22e28). They are characterized with the ability of at-
taching to plastic in cell culture, specific surface antigen
expression and osteogenic, chondrogenic, and adipogenic
differentiation (14,15,29). The cells are used in cardio-
vascular, autoimmune, neurodegenerative, renal and liver
diseases (29,30). However, their renal application is limited
due to the organ complex histopathology, presence of other
diseases such as liver failure, cardiovascular diseases, dia-
betes, inflammation and older age (29). Of note, the effec-
tiveness of MSCs decreases after injection owing to poor
micro-environments. When MSCs are isolated from their
natural niches and cultivated in vitro, they inevitably
confront challenging situations such as low oxygen,
ischemia, food deprivation and free radicals. Hence,
improving the quality of MSCs before injection is an inno-
vative strategy in MSCs-based therapy. In vitro cultivation
of MSCs under the conditions of hypoxia or bioactive mol-
ecules, augmentation of MSCs with cyto-protective factors
via genetic engineering methods and use of modified
conditioned-medium or micro-vesicles could pave the
way of obstacles in stem cell therapy in kidney diseases
(14,16,19,29,31e37).
The present review hopes to comprehensively discuss
clinical trials of MSCs-based therapy in kidney diseases.
Here, we also discuss in vivo studies dealing with MSCs’
survival, proliferation, differentiation and migration. In
addition, MSCs are considered as a new horizon in the
treatment of renal failure. The obstacles and challenges of
this new strategy will be reviewed in the following sections.
Clinical Trials of MSCs in Kidney Diseases
Despite the progress of MSCs-based therapy in the treat-
ment of other diseases, its clinical trials in acute and
chronic kidney injuries remained in primitive steps, and
are associated with some problems.
Although, there are several preclinical studies that prom-
ise the efficiency of MSCs therapeutic application, most of
the studies were limited to clinical trial I/II that investigated
the safety and feasibility of employing these cells in human
(www.clinicaltrial.gov).
Of note, there are only limited clinical data related to
MSCs-based therapy in renal disease. These studies not only
revealed the therapeutic potentials of MSCs, but also inves-
tigated the effects of different protocols in this field. The
dose, route and source of MSCs used for cell therapy are
the factors under the focus of investigations. The routes of
MSCs injection include intravenous, intra-arterial or intra-
renal. The main sources of MSCs in this regard are bone
marrow, umbilical and adipose tissues. There is no unique
protocol regarding to the number of injected cells. In some
clinical trials, the number of injected cells was reported
150e300 million cells twice per week over the course of
2 weeks (38e43). Of note, the number of infused cells was
usually normalized to patient’s body weight (BW).
Table 1 summarizes the registered studies with regard to
clinical trials of MSCs application in kidney diseases. As it
is clear, most of the studies are in the recruitment status and
in phase I/II that shows the first steps in this field. Many other
studies are undergoing and their results are not still revealed.
The first data of a safe and feasible autologous MSCs
administration after kidney transplantation was published
in 2011 (40). In a multistep study conducted by Perico
et al., the effects of MSCs injection before and after kidney
transplantation were investigated in patients at the end stage
of kidney disease. In the first step, patient 1 and 2 received
intravenously 1.7  106 and 2  106 cells/kg autologous
BM-MSCs respectively 7 d after transplantation. Both pa-
tients showed a decrease in creatinine (Cr) level after trans-
plantation; however, a slight creatinine increase was
detected 7e14 d after cell therapy. They reported for the first
time that MSCs infusion acted as an immune-modulator that
could further inhibit memory T cells extension but expand T
regulating cells. However, graft dysfunction occurred after
MSCs transplantation. In the second step of this study, 2
other patients received autologous MSCs at 2  106 cells/
kg concentration intravenously 1 day before kidney trans-
plantation. Control patients did not receive any MSCs. The
patients who received the cell therapy did not show any
negative side effects, and their renal function was restored
3 d after transplantation. Biopsy of the patient number 3 af-
ter 1 year showed interstitial fibrosis and atrophy in tubular
epithelium. Another patient presented severe lymphocyte
infiltration in pre-vascular interestium and tubular epithe-
lium after 1 year. It is suggested that pre-transplant MSCs
rather than those of post-transplantation (after 7 d) could
prevent the acute graft dysfunction in patient 3. Cell rejec-
tion was observed in patient 4 rather than in patient 3 due
to higher HLA haplotype mismatches (40,41).
One of the important problems in solid tissue transplanta-
tion such as kidney is the application of immunosuppressors
after surgery as it seems that MSCs could decrease the dose
of immunosuppressors. In a pilot study conducted by Peng
et al, it was shown that the administration of donors’ bone
marrow-derived MSCs with tacrolimus (50% of standard
dose) was safe enough to protect against acute renal rejec-
tion. They infused the cells in two stages. In the first stage,
the experimental group received 5  106 cells/kg directly
 Mesenchymal Stem Cells and Kidney Diseases 135

Table 1. Clinical trials of MSCs application in kidney diseases (ClinicalTrails.gov)

ClinicalTrials.gov
Identifier Aim of study Enrollment Phase Status

NCT02166489 Safety of MSCs-based therapy in chronic renal failure 6 Phase I Completed

NCT02409940 To Elucidate the effect of MSCs on the T Cell repertoire of the 30 Phase I Recruiting
kidney transplant patients
NCT02266394 To determine if the MSCs infusion prior to percutaneous 42 (estimated) Phase I Recruiting
transluminal renal angioplasty with stenting (PTRA) further
changes in single kidney blood flow and restoration of kidney
function
NCT02561767 Efficacy and safety of bone marrow-derived MSCs inkidney 120 (estimated) Phase I/II Not yet recruiting
transplantation
NCT01429038 Safety and tolerability of MSCs administration after liver or kidney 40 Phase I/II Recruiting
transplantation
NCT00658073 To evaluate autologous MSCs as an alternative for antibody 165 NM Completed
induction therapy in renal transplantation.
NCT00659620 To find out whether MSCs are effective in preventing organ 20 Phase I/II Unknown
rejection and maintaining kidney function.
NCT01840540 Safety and toxicity of intra-arterial-infused autologous 6 Phase I Active, Not
adipose-derived MSCs in patients with vascular occlusive disease recruitment
of the kidney
NCT01275612 To test the feasibility and safety of systemic infusion of donor 9 Phase I Recruiting
ex-vivo expanded MSCs to repair the kidney and improve the
function in patients with solid organ cancers who develop acute
renal failure after chemotherapy with cisplatin.
NCT02195323 To provide confirmation of the safety of MSCs-based therapy in 7 Phase I Completed
chronic kidney disease (CKD).
NCT02808208 To determine the role of autologous adipose-derived MSCs in the 44 Phase I Not yet recruiting
reduction of hemodialysis arteriovenous fistula failure when
applied during the time of surgical creation
NCT02563366 To investigate whether allogeneic bone marrow-derived MSCs can 120 Phase I/II Recruiting
promote function recovery in patients with poor early graft function
after kidney transplantation in china.
NCT02492490 To determine if autologous Stromal Vascular Fraction 120 Phase I/II Recruiting
(SVF)-derived MSC infusion during and after kidney
transplantation
NCT02490020 To clarify the key role of MSCs applied via renal arterial or 260 Phase I Enrolling by
peripheral vein injection to reduce the rejection and delay graft invitation
function (DGF) after renal transplantation.
NCT02563340 To investigate the efficacy and safety of allogeneic bone 60 Phase I/II Not yet recruiting
marrow-derived MSCs (BM-MSCs) on chronic antibody-mediated
rejection (cAMR) after kidney transplantation
NCT02801890 To evaluate the effect of intravenous injection of autologous 10 Phase I/II Recruiting
adipose-derived MSCs in 10 Peritoneal dialysis patients with ultra
filtration failure (UFF).
NCT00752479 Safety and biological/mechanistic effects of the systemic 4 Phase I/II Terminated
intravenous infusion of syngeneic ex-vivo-expanded MSCs in
living-related kidney transplant recipients (one or two HLA
haplotype mismatches) under basiliximab/low-dose RATG
induction therapy and maintenance immunosuppressive drugs.
NCT01539902 Therapeutic effects of hUC-MSCs in the treatment of proliferative 25 Phase II Unknown
lupus nephritis in remission of lupus nephritis (combined partial
and complete remission) in terms of stabilization and improvement
of renal function.
NCT00659217 To evaluate whether MSCs transplantation will improve the lupus 20 Phase I/II Unknown
disease.
NCT02382874 Therapeutic effects of MSCs in the treatment of Idiopathic 5 Phase I Recruiting
Nephrotic Syndrome (INS) and glomerulus disease.

into the renal allograft artery at the time of kidney transplan- increased in the group that received MSCs. It also decreased
tation, and in the second stage, they received 2  106 cells/kg the immunosuppressive drug, increased the survival rate and
intravenously one month later. The number of T-cells improved kidney functions (42).
136 Roushandeh et al./ Archives of Medical Research 48 (2017) 133e146
Table 2. Preclinical studies using hypoxic preconditioned MSCs in kidney injury
References Animal KI model MSCs source
Yu et al, 2013 Rat I/R BM
Overath et al, Mouse Cisplatin Adipose
2016
Zhang et al, Rat I/R Human
2014 adipose tissue
Liu et al, 2012 Mouse I/R BM
BM, bone marrow; b-FGF, Beta fibroblast growth factor; IGF-1, insulin growth factor; NGAL, Neutrophil gelatinase-associated lipocalin; IL-b, interleukin-b;
IL-6, interleukin 6; Casps3, caspase 3; Akt, Protein kinase B; SDF-1, stromal-derived factor-1; CXCR4, chemokine receptor; I/R, ischemic/reperfusion.
In another clinical trial, 76 patients underwent live-donor
renal transplantation and received donor stem cells before
transplantation. All patients received donor hematopoietic
stem cells (17.4  5.5  108 nucleated cells/kg BW of recip-
ient with mean  SD CD34þ count of 2  0.7  104/kg BW)
and 55 patients received donor adipose tissue-derived MSCs
(CD45/90þ cells of 5.8  1.5  104/kg BWand CD45/73þ
cells of 1.1  0.92  104/kg BW) via omental vein. All
patients were treated with cyclophosphamide, rabbit-
antithymocyte globulin and rituximab. In addition, depend-
ing on the patient’s condition, other drugs such as total
lymphoid irradiation, bortezomib and methylprednisone
were applied. Immunosuppressors such as calcineurin inhib-
itor (CNI), cyclosporin, tacrolimus, sirolimus, mycofenolate
sodium, azathioprine and prednisone were used. All Immu-
nosuppressive drugs except for prednisone were successfully
withdrawn in all patients. On top of that, no organ rejection or
negative effects were detected after the drug withdrawal, and
the creatinine level remained normal and constant over the
withdrawal of the immunosuppressive drugs (43). Renal fail-
ure usually accompanies with other diseases such as cardio-
vascular disease that make the treatment even more
complicated. Primary results released by Gooch et al.
showed that the infusion of low dose of allogenic
BM-MSCs into supra-renal aorta could prevent all symptoms
in 5 patients with acute kidney injury induced after cardio-
pulmonary bypass. It also decreased the incidence of AKI
and shortened the hospitalization period (29,44). These re-
sults were consistent with the findings of Togel and Westen-
felder’s study that reported the reno-protective effects of
intracoronary injection of allogenic BM-MSCs in patients
under cardiac surgery with high risk of AKI (45).
In another ongoing clinical trial in the stage of recruiting
participants, 70 renal allograft recipients, between
18e75 years old, were recruited in a Phase II, open label,
randomized non-blinded, prospective, single center clinical
study. The mentioned study was designed to investigate the
efficiency and safety of employing concentration-controlled
everolimus and MSCs (everolimus/MSC group) as well as
everolimus with standard tacrolimus (everolimus/standard
dose of tacrolimus group). Hence, 35 patients participated
% oxygen Outcomes
200 mmol/l [ Cell engraftment, survival, proliferation, renal function,
cobalt chloride24 h b-FGF and IGF-1 over-expression
48h, 0.5% O2 Y Serum creatinine, NGAL, IL-b and IL-6
[ Cell survival
1% O2 24h Y Oxidative stress, Casp3 down-regulation
[ Akt phosphorylation, Angiogenesis, Antioxidants capacity
%3 O2 24h [ Migration, homing and mitogenic responses, Renal function,
SDF-1-CXCR4/CXCR/7Apoptosis Y
in the everolimus/MSC group, and 35 others took part in
the everolimus/standard dose of tacrolimus group. The pa-
tients received 2 doses of 1e2  106 cells/kg autologous
BM-MSCs intravenously combined with everolimus, pred-
nisolone and tacrolimus with 7 d of time interval 7 weeks
after transplantation. In the second MSCs injection, tacroli-
mus was reduced to 50% and completely deleted after
1 week. Control group was treated with routine protocol
including everolimus, prednisolone and standard dose of ta-
crolimus. The aim of the study was to compare some fac-
tors including fibrosis, acute rejection, graft loss or death,
renal function, proteinuria, infections, and immune moni-
toring between the two groups under study (Trial registra-
tion: NCT02057965) (18).
Application of Modified MSCs in Preclinical Studies:
In vitro Cultivation and Augmentation of MSCs and
their Preclinical Studies in kidney Disease
A plenty of animal studies reported MSCs reno-protective
effects on both models of acute and chronic injuries. These
studies varies in terms of MSCs sources, dose of adminis-
tration, route of injection, type of kidney injury and pre-
treatment of cells under different in vitro conditions
before their administration (3,12,16,34,37). Application of
Modified MSCs is a novel strategy that is attractive to sci-
entists in preclinical and even clinical studies (21,33).
The Tables 2e5 summarize some preclinical studies on
the application of Modified MSCs or MSCs-derived micro-
vesicles in the treatment of kidney disease.
In this section, some studies will be reviewed that are
dealing with in vitro treatment of MSCs with hypoxia or
some bioactive molecules, MSCs genetic modifications
and the role of micro-vesicles in order to enhance the effi-
ciency of MSCs-based therapy in kidney injuries.
Hypoxia
MSCs are usually cultivated in normoxic condition with
20% O2 concentration in vitro. However, O2 concentrations
are different among tissues which are the sources of these
 Mesenchymal Stem Cells and Kidney Diseases 137

Table 3. Preclinical studies on the pretreatment of MSCs with some bioactive molecules in kidney injury

Preconditioning
References Animal KI model MSCs source modality Outcome

Mias et al, 2008 Rat I/R Adipose Melatonin [ Cell survival, Proliferation, Renal function, SOD-
1 and catalase, [Angiogenesis, YFibrosis
Zhao et al, 2015 Human Cisplatin Human Melatonin [ Cell proliferation, Survival, Migration, Reno-
kidney cells Adipose MSC Protection YInhibition of apoptosis
Chen et al, 2014 Rat Sepsis Adipose Melatonin Y Oxidative stress, Fibrosis, YApoptosis,
[Antioxidants
Xinaris et al, 2013 Mouse Cisplatin BM IGF-1 [ Cell engraftment, SDF-1-CXCR4 pathway
YRenal morphology changes
Liu et al, 2013 Rat Gentamyin BM Vitamin E Y Creatinine, Urea, Tubular epithelium damage,
Apoptosis
Cai et al, 2014 Rat I/R BM Atorvastatin Y Creatinine, Urea, Apoptosis, Oxidative stress,
Inflammatory responses
[ Proliferation in tubular epithelium
Turnsek et al, 2016 Mouse Cisplatin Wharton’s jelly Antithymocyte [ Restored morphology, Antioxidants SOD-1, HO-1
Globulin and GPx, Survival of mice
Y Creatinine, Urea, Apoptosis, Oxidative stress

BM, bone marrow; I/R, ischemic/reperfusion; SOD1, superoxide dismutase 1; SDF-1, stromal derived factor 1; CXCR4, chemokine receptor; HO-1, Heme
oxygenase; GPx, glutathione peroxidase.

cells. O2 concentration in MSCs niches varies from 2e8%
(37). Therefore, it seems that MSCs culture under routine
culture conditions can change the behavior of these cells
by disturbing both the DNA and protein structures and
consequently alter their functions (37,46,47).
Hypoxic preconditioning was confirmed by several
research groups as an effective strategy to activate MSCs
and enhance their therapeutic efficacy to be employed in
ischemic diseases. Injection of human adipose tissue-
derived MSCs pretreated with 1% hypoxia could decrease
the oxidative stress and enhance the antioxidants of MSCs.
Furthermore, it protects the cells against apoptosis, downre-
gulates Casp3 and increase anti-apoptotic factors and Akt
phosphorylation (16). Administration of hypoxia pre-
conditioned MSCs significantly increased vascular density
in ischemic kidney tissues compared to non-conditioned
group (16).
Hypoxic preconditioning of MSCs resulted in less
tubular cell necrosis, loss of brush border and tubular dila-
tion following MSCs-based therapy (16). Creatinine and

Table 4. Shows the application of gene-engineering modified-MSCs in preclinical studies in Kidney injury

MSCs Gene- modified

Reference Animal KI model source MSCs Outcome

Mohammadzadeh-vardin Rat Cisplatin BM Nrf2-MSC [ Renal function, Morphological features of kidney,

et al, 2015 Growth factors and antioxidants YCreatinine, Urea
Zhaleh et al, 2016 Rat Glycerol BM Nrf2-MSC YCratinine, Urea, Kim-1 and Cystatin C
[ Renal function, AQP1 and CK-18
Halabian et al, 2015 Rat Cisplatin induced BM Lcn2-MSC [ Reno-protection property, Growth factors,
injury in renal cells antioxidants, Cell proliferation
Y Apoptosis
Hagiwara et al, 2008 Rat I/R BM TK-MSC [ Renal function, Renal tubular epithelium repair
Y Apoptosis, Nitric oxide, Inflammation
Liu et al, 2013 Rat I/R BM CXCR4-MSC [ SDF-1, Cell engraftment, Renal function, Activation
of PI3K/AKT and MAPK pathways, TGF-B1
Liu et al, 2016 Rat Gentamycin hUCMSC IGF-1-MSC [ Cell migration, Renal function, Activation of
antioxidants, anti-inflammatory and anti-apoptotic
signal pathways
Yuan et al, 2011 Mouse Cisplatin BM VEGF-MSC [ Proliferation, Angiogenesis
Y Apoptosis
Wang et al, 2016 Rat Mercuric chloride BM CXCR4-MSC [ CXCR4, homing of injected cell

BM, bone marrow; Nrf2, Nuclear factor erythroid-2 related factor 2; Kim-1, kidneyinjury molecule-1; AQP1, aquaporin 1; CK18, cytokeratin-18; Lcn2,
lipocalin 2; SDF-1, stromal derived factor 1; P13K/AKT, Phosphatidylinositol-4,5-bisphosphate 3-kinase/Protein kinase B; MAPK, Mitogen-activated pro-
tein kinase; TGF-B1, transforming growth facor-B1; CXCR4, chemokine receptor; VEGF, vascular endothelial growth factor; IGF-1, insulin growth fac-
tor; TK, tissue kallikrein; Lcn2, lipocalin 2.
138 Roushandeh et al./ Archives of Medical Research 48 (2017) 133e146

Table 5. Illustrates the evidence of MSCs-derived micro-vesicles application in Kidney regeneration in preclinical studies

References Animals KI model type MSCs SI or MI Pretreatment Outcome

Zou et al, 2014 Rat IRI (Unilateral) Human (WJ) SI No Y Apoptosis, Fibrosis, Inflammation, CX3CL1
[ Proliferation, Renal function
Wang et al, 2015 Mouse UUO mouse (BM) SI erythropoietin Y Changed miRNA profile Fibrosis, Apoptosis
Bruno et al, 2012 Mouse Cisplatin (lethal dose) Mouse SI and M No [ Renal morphology, Tubular cell proliferation,
(6 times) [ Mouse mortality, BUN and Creatinine
Ju et al, 2015 Rat IRI (Unilateral) hUC-MSC SI No [ Restored renal structure and function, Tubular
cell dedifferentiation and growth, Rat HGF
expression
Y Apoptosis
Reis LA et al, 2012 Rat Gentamycin BM SI RNAase and Y Cr, Urea and FENA, necrosis and Apoptosis,
Trypsin RNAase application on reno-protective effects
[ Cell proliferation
Zhou et al, 2013 Rat Cisplatin hUCMSCs SI No [ Renal function, Morphology, Proliferation
Y Oxidative stress, Renal tubular apoptosis
Bruno et al, 2009 Mouse Glycerol BM SI RNAase [ Renal function, Restored renal morphology
Y Creatinine, Urea, RNAase application on
reno-protective effects
Gattie et al, 2011 Rat I/R BM SI No Y Creatinine, Urea, Apoptosis
[ Proliferation, Protection kidney against CKD
Zhang et al, 2016 Rat IRI hWJMSC SI No [ Nrf2/ARE pathway, SOD-1 and HO-1,
restored renal morphology
Y ROS, Creatinine, Urea
Kilpinen et al, 2013 Rat Hypoxia induced hUCBMSC SI IFN-y Diverse Rab proteins, complement and MHCI,
kidney injury no reno-protection

IRI, ischemic/reperfusion injury; SI, single injection; MI, multiple injection; CX3CL, chemokine ligand 1; BUN, Blood urea nitrogen; HGF, hepatocyte
growth factor; Cr, creatinine; FENA, Fractional Excretion of Sodium; CKD, chronic kidney disease; Nrf2/ARE, Nuclear factor erythroid-2 related factor
2/antioxidant respond element; SOD-1, super oxide dismutase; HO-1, heme oxygenase; ROS, reactive oxygen species; MHCI, Major histocompatibility com-
plex; UUO, unilateral ureteric obstruction; WJ, wharton jelley; hUCB, human unbilical cord blood.

BUN decreased in the serum of animals that received
MSCs specially those preconditioned with hypoxia. It is
suggested that hypoxia could enhance the efficiency of
MSCs through anti-apoptotic effects, ROS scavenging
and angiogenesis (16).
Recently conditioned medium instead of MSCs was
used in cell therapy. Hypoxia preconditioning of mouse ad-
ipose tissue-derived MSCs was performed with 0.5% O2.
Conditioned medium of hypoxia-pretreated adipose
tissue-derived MSCs from peri-renal fat developed regener-
ation in mouse models of cisplatin-induced AKI (cisAKI).
The MSCs significantly decreased serum creatinine and
neutrophil gelatinase-associated lipocalin values. Moreover,
two inflammatory cytokine, i.e. IL-1 b and IL-6 were
declined in serum indicating its immunomodulatory effects.
Cell survival was more in hypoxia preconditioned group
over 3 d after injection. Kidney injury markers such as renal
KIM-1, Klotho and HMGB-1 were changed after cisplatin
administration. Downregulation of HMGB-1 could sup-
press the immune response in injured tissues (48).
Cobalt choloride was also used to induce hypoxia. Cul-
ture of rat bone marrow-derived MSCs (BM-MSC) with
200 mmol/L cobalt significantly increased the expression
of HIF-1 a and CXCR4 and leaded to the increased migra-
tion of MSCs in vitro (49,50). Blocking of these proteins
such as HIF-1 with their targeting siRNA declined cell
migration. Hypoxia mimetic preconditioned MSCs (HMP-
MSC) showed better engraftment in kidney ischemic model
compared to non-preconditioned MSCs (NP-MSC). Super-
paramagnetic iron oxide (SPIO) and fluorescent-labeled
MSCs were followed by magnetic resonance imaging and
immunohistochemistry respectively. Imaging clearly
showed that HMP-MSCs exhibited greater migration and
a longer retention time in the ischemic kidney than
NP-MSCs. Histologically, 72 h after cell infusion, no cell
was detected in kidney of NP-MSC but still remained in
glumerulli and tubulointerstum in HMP-MSC, 1 week after
cell therapy. Overall, it was confirmed that hypoxia could
increase survival and proliferation and developed kidney
functions. Creatinine and urea levels decreased in both
groups of cell therapy; however, HMP-MSCs had better ef-
fects on renal recovery. Hypoxia exerts its reno-protective
effects through paracrine secretion such as b-FGF and
IGF-1 (33).
It is reported that hypoxia preconditioning may have a
role in chemotaxis and homing of MSCs. The mechanism
is mediated by SDF-1-CXCR4/CXCR7 axis. The interac-
tion of SDF-1 and its receptor CXCR4 expressed on the
MSC surface plays an important role in the migration of
transplanted cells. MSCs homing decreased when the
CXCR4 or CXCR7 inhibitors were used. HP-MSCs (3%)
migrated to the ischemic kidney more efficiently than
 Mesenchymal Stem Cells and Kidney Diseases
NP-MSCs resulting in remarkably improved renal func-
tions, accelerated mitogenic responses, and reduced cell
death. Histologically, cell therapy groups had less nephro-
toxicity, more proliferation and less apoptosis compared
to the control group (50).
MSCs Preconditioning with Bioactive Molecules
Cytokines, growth factors and other bioactive molecules
have a critical role in the survival, migration and differen-
tiation of MSCs.
One of the main problems in cell therapy is the early
death of injected cells because of oxidative stress (51). It
is confirmed that melatonin hormone is able to remove
oxidative damage and stimulates cytokine secretion in
injured tissues (52,53). It acts as antioxidant, anti-
apoptotic and anti-inflammatory agent (54e56). Pretreat-
ment of rat MSCs with melatonin enhanced cell survival
and proliferation in AKI mostly through the cellular recep-
tors MT1 and MT2. Histological analysis showed no exces-
sive production of extracellular matrix, collagen, calcium
deposition or fibrosis in kidney tissue after 2 months. In
addition, Melatonin-treated cells increased the expression
of two important antioxidants, i.e. superoxide dismutase 1
(SOD1) and catalase. It also over-expressed beta fibroblast
growth factor (b-FGF) and hepatocyte growth factor
(HGF), the two factors in angiogenesis process. Further-
more, it improved renal function by decreasing both Cr
and BUN levels in rat ischemic/reperfusion (I/R) renal fail-
ure. It seems that melatonin is an efficient choice in MSCs-
based therapy because it is currently used as a complement
with no side effects in human (57). Conditioned medium
collected from pretreated human adipose tissue-derived
MSCs culture with melatonin for 3 hours showed reno-
protective effects on cisplatin-induced injury in human kid-
ney cells (58). Pretreated conditioned medium not only
enhanced the rate of MSCs proliferation, survival and
migration, but also inhibited apoptosis through up-
regulation of phosphor-p44/42 MAPK (P-Erk1/2), Bcl-2,
SOD-1 and heme oxygenase 1 (HO-1) (58).
Melatonin also has reno-protective effects in sepsis-
induced AKI and decreases kidney injury through
increasing antioxidants such as glutathione reductase
(GRþ), glutathione peroxidase (GPxþ), HO-1 and quinine
acceptor oxidoreductase 1 (NQO-1þ), decreasing oxidative
stress NADPH oxidase -1 (NOX-1) and NOX-2 and
declining in fibrosis factors Smad3 and TGF-b. It also in-
hibits apoptosis by changing gene expression of cleaved
Caspase 3, Poly ADP (Adenosine Diphosphate)-Ribose
Polymerase (PARP) and mitochondrial Bax (59).
Homing of MSCs in injured tissues is very critical in cell
therapy. Most of the injected cells are attracted to lung after
transplantation. Pretreatment of mouse BM-MSCs with in-
sulin growth factor 1 (IGF-1) significantly increased the
capability of cell engraftment in cisplatin-induced kidney
139
injury. In addition, after IGF-1 pretreatment, the cells
mostly settled in peritubular and rarely in renal tubular
epithelium. The injected cells were observed for a short time
in glomerulus of injured kidney after IGF-1 pretreatment.
Adversely, pretreatment with other factors such as glial cell
line-derived neurotrophic factor (GDNF) and tumor necro-
sis factor 1 (TNF-a) did not enhance the engraftment of
MSCs in animal model of AKI. The mice receiving IGF-
1-pretreated MSCs showed more decline in cast formation,
tubular epithelium necrosis and less changes in ultrastruc-
ture of tubular tissues. It is suggested that the activation of
SDF-1-CXCR4 is the mechanism by which IGF-1 could
induce its potency and enhance renal function (38).
Gentamysin is a toxic antimicrobial drug that its applica-
tion increased recently because of microbial resistance (60).
It causes nephrotoxicity, and results in loss of kidney func-
tion (61). Application of MSCs with vitamin E could pro-
tect its toxic effects. Vitamin E is an oxygen free radical
scavenger and lipid-soluble antioxidant (62). The rats
receiving MSCs and vitamin E presented the lowest serum
creatinine but no change in urea nitrogen decline. Vitamin
E protected the kidney against gentamycin toxicity through
decreasing tubular epithelium necrosis and dilation, brush
border loss and suppressing immune responses. Electron
microscopy showed that gentamycin induced apoptosis in
renal tubular epithelial cells (RTECs). The combined strat-
egy of cell therapy and vitamin E improved and restored the
morphology of injured tissue according to ultrastructure
findings through increasing the number of organelles and
decreasing the cytoplasmic vacuoles. Nevertheless, the
changes were not significant when MSCs was used alone.
Downregulation of some apoptotic genes such as caspase
3 and 9 is the mechanism by which vitamin E could exert
its potency in combination with MSCs. It is suggested that
the application of MSCs along with vitamin E could have
better therapeutic effects on AKI rather than MSCs and
vitamin E, separately (63).
Pretreatment of MSCs with Atorvastatin could enhance
renal functions by decreasing apoptosis and ROS. It also in-
hibited the immune response (64).
Antithymocyte globulin (ATG) is an immunosuppressor
that effectively enhances the renal function when adminis-
tered on hWJMSC before transplantation into mouse models
of cisplatin-induced AKI. ATG increased antioxidants such
as SOD-1, HO-1 and GPx. More interestingly, it decreased
the mortality rate of mice injured with cisplatin (65).
Application of Genetically-modified MSCs in Kidney
Diseases
MSCs could be engrafted in injured tissues and are the best
vehicle for gene transfer in cell therapy. Genetic manipula-
tion of MSCs could induce the secretion of some proteins
involved in cell migration, proliferation and survival.
Different genes could be introduced into MSCs through
140 Roushandeh et al./ Archives of Medical Research 48 (2017) 133e146
viral or non-viral vectors. The later technique is safer, but
its efficiency is low. In this section, some genetic modifica-
tions will be reviewed that resulted in the development of
MSCs therapeutic properties.
The nuclear factor erythroid-2 related factor 2 (Nrf2) is
an important transcription factor that protect the cells
against stresses. Transplantation of Nrf2-engineered MSCs
(Nrf2-MSCs) decreased cisplatin-induced injury in rat
models of AKI. It also decreased the cytotoxic effects of
cisplatin on MSCs in vitro. Nrf2-MSCs could ameliorate
the creatinine and urea levels and enhance renal function
in AKI. Nrf2 overexpression improved the morphological
features of renal tubule damaged by cisplatin. Expression
of growth factors and antioxidants leaded to better therapeu-
tic efficiency of Nrf2-MSCs (66); however, its potency for
tumorigenicity should be considered. Transplantation of
Nrf2-MSCs into glycerol-induced AKI rats enhanced renal
function by decreasing the creatinine and urea levels 14 d af-
ter cell therapy. More interestingly, the repaired genes such
as Aquapoin 1 (AQP1) and Cytokeratin 18 (CK-18) were
overexpressed in the group that received MSCs or saline
alone. Moreover, the renal damage markers, i.e. kidney
injury molecule 1 (Kim-1) and Cystatin C decreased signif-
icantly after the application of Nrf2-MSCs (3). Actually, the
therapeutic effects of Nrf2 could be exerted through the
expression of genes involved in detoxification, anti-
oxidation and immunomodulation (3,67,68).
Overexpression of lipocalin2 in MSCs enhanced their ef-
ficiency in in vitro studies (69). Lcn2 belongs to a family of
soluble proteins that is expressed in various normal and path-
ologic conditions. It increased to 1000 fold after renal tu-
bules injury (70). It is reported that lipocaline2 is normally
expressed under some conditions such as stress and inflam-
mation. It plays a pivotal role in physiological processes such
as cell proliferation, senescence and apoptosis (69,71e77).
It is shown that the co-culture of bone marrow-derived
MSCs overexpressing lipocalin2 with HK-2 and
HEK293 cells had reno-protective potential against
cisplatin-induced injury. Lcn2-Overexpressed MSCs
increased the proliferation rate and prevented cisplatin-
induced apoptosis when co-cultured with renal cell lines.
It increased the expression of growth factors such as
HGF, IGF, TGF-b, and FGF as well as antioxidants such
as SOD1, HO-1 and MT-1 in the kidney cells. Therefore,
it is suggested that the protective effects of this protein
could be presented through the secretion of growth factors
and production of antioxidants (78).
Tissue kallikrein (TK) was first discovered in human
urine as a hypotensive substance (79). It is remarkably
reduced in mild kidney disease and severe renal failure
(80). It is reported that kallikrein has protective effects on
tissues damaged by oxidative stresses. Kallikrein-MSCs
implantation increased protection against AKI through
decreasing apoptosis and inflammation. Tissue Kallikrein-
MSCs improved renal function by decreasing creatinine
and urea level and tubular epithelium repair. Six hours after
I/R, TK-MSC implantation significantly reduced renal cell
apoptosis in association with decreased inducible nitric ox-
ide synthase expression and nitric oxide levels. 48h after
cell therapy, TK-MSCs inhibited the infiltration of the in-
flammatory cells and decreased myeloperoxidase activity,
superoxide formation and p38 mitogen-activated protein ki-
nase phosphorylation. Furthermore, it reduced the ex-
pression of tumor necrosis factor-a, monocyte
chemoattractant protein-1 and intercellular adhesion
molecule-1. It is suggested that kallikerin could present
its therapeutic effects through the control of apoptosis
and inflammation (81).
MSCs engraftment to target injured tissues is very crit-
ical in the outcome of cell therapy. Stromal cell-derived
factor-1 (SDF-1) and its cellular receptor, CXCR4, have a
pivotal role in stem cells migration toward injured tissues,
but the expression of CXCR4 on the surface of BMSCs is
not high. Therefore, overexpression of this receptor on
the surface of MSCs is a new strategy to increase the effi-
ciency of cell therapy. The CXCR4- BMSCs showed a
remarkable expression of SDF- 1 in AKI. CXCR4- BMSCs
transplantation significantly increased the number of en-
grafted BMSCs in the ischemic renal tissue resulting in
the improvement of renal functions (82). Activation of
PI3K/AKT and MAPK in BMSCs by SDF-1/CXCR4 axis
could explain the mechanism involved in this process
(82,83).
Overexpression of TGF-b1 in genetically-engineered
MSCs increased the homing of the cells in ischemic models
of kidney disease and improved the renal function by
decreasing both the creatinine and urea levels. This study
confirmed the role of TGF-b1 in controlling the SDF-1-
CXCR4 axis in cell engraftment (84).
IGF-1 secreted by MSCs could enhance their therapeu-
tic potential through cell proliferation and anti-apoptotic
actions. After transplantation of modified human umbilical
cord (UC)-derived MSCs-IGF-1 to gentamycin-induced
AKI, more cell migration was observed in kidney tissue
compared to MSC-vector or MSCs. It also increased
renal function through recovering the serum and urine
biochemical indices. Less histological damage to glomer-
ulus, tubular epithelium and collecting tubules were
observed after the application of human UC-MSCs-IGF-
1. It also up-regulates some signaling pathway genes
involved in the properties of anti-oxidation, anti-inflamma-
tory, anti-apoptotic and cell migratory capacities of
UC-MSCs-IGF-1 (36) (Figure 1).
It seems that vascular endothelial growth factor (VEGF)
could have a critical role in reno-protection (85). Human
MSCs modified with VEGF could enhance the proliferation
of nude mouse kidney epithelial cells injured by cisplatin. On
the other hand, it inhibited apoptosis in renal tissue. Interest-
ingly, no difference was detected between the migration of
MSCs and MSC-VEGF. Angiogenesis was induced after
 Mesenchymal Stem Cells and Kidney Diseases 141

the transplantation of MSC-VEGF in vivo, and the peritubu-
lar capillary density increased in this group (86).
Table 4 shows the application of gene engineering
modified-MSCs in preclinical studies in Kidney injury.
MSCs and their Micro-vesicle Application in Kidney
Diseases
Membranous small vesicles or micro-vesicles (MVs) are
released by MSCs (87e90). They are extracellular vesicles
including exosomes and micro-vesicles. Exosomes derived
from endocytic vesicles have a diameter of 30e100 nm. Shed-
ding vesicles, also named ectosomes or membrane particles
tending to be 100 nme1 mm in diameter. They bud directly
from the plasma membrane. Most extracellular vesicles are
heterogeneous and consist of exosomes and shedding vesi-
cles, collectively defined as micro-vesicles (MVs) (90e92).
MVs play a critical role in cell-cell communications.
MVs interact with target cells through surface-expressed li-
gands, and transfer surface receptors that deliver proteins,
messenger RNA (mRNA), microRNA (miRNA), and bioac-
tive lipids. They contain high amounts of phosphatidylser-
ine- a protein associated with lipid rafts, and are full of
cholesterol, sphingomyelin and ceramide (34,92).
MVs deliver complex and bioactive molecules derived
from MSCs to injured cells leading to tissue regeneration.
They do not represent histocompatibility antigens;
therefore, multiple administrations of allogeneic MVs
may not activate the immune response (92).
MVs exert their effects directly on cells through transfer-
ring cell surface receptors or epigenic reprogramming.
Considering these characters and benefits, MVs would be
very attractive in the treatment of renal failure
(88,90,93,94).
Table 5 summarizes some preclinical studies on the
application of micro-vesicles in the treatment of kidney
injuries.
Erythropoietin (EPO) is a glycoprotein hormone that in-
volves in the formation and differentiation of erythroid pre-
cursor cells in the bone marrow (95). It is expressed in some
tissues such as renal tubular cells which also express EpoR
and respond to EPO treatment (96). MVs derived from
MSCs pretreated with EPO showed significantly restored
morphology features of renal tissue injured by Unilateral
Ureteral Obstruction (UUO) model on 7 and 14 d. It
enhanced kidney function by decreasing urine and creati-
nine levels one day after therapy. Extracellular matrix depo-
sition and fibrosis declined in mice that received MVs-EPO.
It is reported that the expression of a-smooth muscle actin
(a-SMA) as a myofibroblast marker decreased while E-cad-
herin as an epithelial cell marker increased after the appli-
cation of MVs-EPO (32).
microRNA profiling array results found remarkable
changes in the profile of MVs-MSC and MVs-EPO.

Figure 1. Showes the genes that changed after overexpression of some genes in MSCs. GEM-MSCs, genetic engineering modified-mesenchymal stem cell;
Nrf2, Nuclear factor erythroid-2 related factor 2; Lcn2, lipocalin 2; TK, tissue kallikrein; CXCR4, chemokine receptor; IGF-1, insulin growth factor1; TGF-
B1, transforming growth factor B1. (A color figure can be found in the online version of this article.)
142 Roushandeh et al./ Archives of Medical Research 48 (2017) 133e146
EPO-MVs changed the expression of 212 miRNAs
including miR-299, miR-499, miR-302, and miRNA-200
from which 70.28 % were overexpressed (32).
A single administration of MVs immediately after
ischemic AKI in animal models ameliorated renal injury
at both acute and chronic stages (34). The anti-
inflammatory effect of MVs seems to be exerted through
the suppression of CX3CL1. This establishes a substantial
foundation for future research and treatment. Application
of human wharton’s jelley MSCs-MVs (hWJMSC-MVs)
in AKI rats decreased renal cell apoptosis and induced cell
proliferation. It also decreased immune responses in the
early stages through decreasing the number of
CD68þ macrophages in the kidney and suppressing
CX3CL1. Additionally, it enhanced renal tissue restoration
and inhibited fibrosis leading to the improvement of renal
function. It is suggested that some mirRNAs such as mir-
15a, mir15b, mir-16, mir195, mir424 and mir497 are the
targets for CX3CL1. These microRNAs might control
CX3CL1, but their functions are not that clear yet (34).
It is suggested that multiple injections of MVs (miMVs)
are more efficient than single that of MVs (siMVs). In a
study, mouse BM-MSCs-derived miMVs enhanced the sur-
vival of SCID mouse as a model of AKI. It also restored
renal tissue and increased renal function for a long time
(21 d). It seems that the expression of anti-apoptotic gene
after MVs application is the main mechanism of this phe-
nomenon (89).
Dedifferentiation of renal tubular cell epithelium is
important in the repair process after kidney injury. It was
revealed that hepatocyte growth factor has a critical role
in this regard. Human umbilical cord (HU) MSCs could ex-
press this growth factor. Furthermore, MVs-HUC MSCs
could deliver their RNA into the injured tubular cells and
enhance the gene expression of hepatocyte growth factor re-
sulting in cell regeneration. They exerted therapeutic effects
on renal cells through anti-apoptotic and anti-fibrotic activ-
ities as well as dedifferentiation. Human HGF mRNA car-
ried by micro-vesicles can reside in renal tubular cells and
were able to induce higher production of this protein in
injured tubular epithelium. Interestingly, MVs treatment
with RNAase eliminated all its reno-protective effects. Vi-
mentin and proliferating cell nuclear antigen (PCNA) pro-
teins increased in tubular epithelium of injured kidney
after MVs treatment. Vimentin and PCNA up-regulations
leaded to an increase in dedifferentiation and cell growth
respectively. MVs activates Erk1/2 pathway to induce
dedifferentiation and growth. An Erk1/2 inhibitor could
block the production of HGF and disturb renal repair (35).
Exosomes are micro-vesicles that are released from
various cells into the extracellular space when intracellular
MVBs fuse with the plasma membrane of the cells (87). It
is shown that exosomes derived from human umbilical cord
MSCs has reno-protective effects on cisplatin-induced renal
injury through ameliorating the creatinine and urea levels.
It could improve the proliferation of renal epithelial cells
and inhibit apoptosis. It also recovered the morphology of
proximal tubules and decreased cast formation. Human um-
bilical cord MSCs-derived exosomes (hUCMSC-exosome)
decreased two oxidants, i.e. 8-hydroxy-20 -deoxyguanosine
(8-OHdG) and malondialdehyde (MDA) and increased the
level of a critical antioxidant, i.e. Glutathione (GSH).
hUCMSC-exosome inhibited p38MAPK pathway and inac-
tivated apoptosis process (97).
Therapeutic effect of MSCs is suggested to be mediated
by paracrine interactions with immune cells. It is found that
human umbilical cord blood MSCs (hUCBMSC)-derived
MVs pretreated with interferon-gamma (MVs-IFN-g) had
no therapeutic effects on I/R-induced kidney injury. It
was not able to decrease creatinine and urea levels, and
no improvement in the recovery of kidney tissue was
observed while hUCBMSC MVs had reno-protective ef-
fects on ischemic injury in kidney. Moreover, protein con-
tent in MVs-IFN-y was significantly higher than that in
non-pretreated MVs (448 proteins versus 220). They pre-
sented diverse Rab proteins and complements and ex-
pressed MHCI. It was concluded that the same cell could
produce different types of MVs according to the external
signals (98).
It seems that antioxidant properties of MVs-derived
MSCs could enhance renal recovery. It was reported that
the application of conditioned medium of human Wharton’s
Jelly mesenchymal stromal cells could activate Nrf2/anti-
oxidant response element (ARE) in ischemic-induced kid-
ney injury. It increased SOD and HO-1 and decreased
ROS along with Nrf-2 and ARE. MVs efficiently restored
renal morphology and function through the decline of creat-
inine, urea and NGAL (99).
The Challenges of MSCs Application in Kidney Repair
Although the application of MSCs is very promising in kid-
ney repair, its therapeutic potentials confront some limita-
tions that need more attention in the future.
Unfortunately, there is no updated and adequate good
manufacturing practices (GMP) guideline in MSCs-based
therapy in kidney. In addition, other issues including
ethical, legal, technical and safety concerns must be care-
fully considered (91).
Although there is no report on the detrimental effects of
MSCs-based therapy in clinical trials and it is considered
safe and feasible, more uncontrolled factors should be
considered in cell therapy of kidney diseases (27).
Mal-differentiation of stem cells is another challenge
that not only impairs the renal tissue recovery, but it also
exacerbates the renal injury by replacing ectopic cells in
kidney. Differentiation of injected MSCs to adipocytes
could lead to chronic renal injury (92).
Route of MSCs injection is another issue that should be
considered in renal treatment. Intravascular administration
 Mesenchymal Stem Cells and Kidney Diseases
of MSCs could lead to vascular occlusion (100). Intrave-
nous injection attracts the cells to lung tissues and de-
creases its accurate homing in renal tissue (100).
Although the clinical trials of MSCs application are
promising, their administration is limited in some dis-
eases. Their employment to treat various diseases such
as kidney should be with some considerations. More re-
searches are needed to find out the mechanisms and bio-
logical properties of MSCs to pave the way of their
application. MSCs are heterogeneous in population and
may result in different outcomes. MSCs ex vivo culture,
their culture protocol and environment, source of the cells,
number of cellular passages, cell number injection are fac-
tors of vital importance that should be all standardized and
optimized (21,101). To obtain better outcomes, more ran-
domized and controlled multicenter clinical trials are
necessary (101).
Due to the low survival and engraftment of MSCs after
transplantation, a high dose ranging from 150 million to
300 million cells is usually used in clinical trials adminis-
tered twice per week over the course of 2 weeks (89). This
might result in transfusion reaction such as allergic reac-
tion, fever, hypotension and infection. Infection is very crit-
ical; therefore, donor members must be thoroughly
examined before bone marrow aspiration (89).
Tumorigenecity is another concern after cell therapy.
Although there has been no malignancy report in clinical
trials, it should be noticed that most trials have a short
follow up. Hence, long term follow up is necessary to
assure in this regard (101).
Micro-vesicles and exosomes have valuable therapeutic
effects on renal tissue recovery after injury; however, their
application should be carefully monitored. It was reported
that miRNA transported by exosomes involve in cancer
occurrence (102). They might also increase the risk of neuro-
degenerative disorders such as prion, tauopathies, Alz-
heimer’s and Parkinson’s diseases. We are not sure whether
all of the MVs cargos are useful in cell therapy or not. There-
fore, finding their complexity, components and interactions
with other secreted factors should be studied (90e92).
Application of MVs as a non-cellular therapy should be
improved. Therefore, several factors such as the type of
MVs’ effector molecules, cell source, mechanisms of tar-
geting to specific tissues and the genetic manipulation of
the cells they are derived from should be considered to
enrich the therapeutic potentials of MVs before clinical
application in human (90).
Overall, some challenges such as large-scale production
of MVs from cultured stem cells as well as the criteria for
the potency of different MVs preparations should be ad-
dressed before any clinical use. Although the safety of
MVs was confirmed in preclinical experiments, further
studies are recommended in this regard.
143
MSCs-based Therapy as a New Horizon for Treatment of
Kidney Diseases
MSCs-based cell therapy is a promising therapeutic
approach in heart, neurodegenerative and autoimmune dis-
eases. However, kidney diseases have complicated histo-
pathological configurations that make its routine
applications even more difficult. Thus, the final outcomes
are usually not favorable.
Application of bone marrow-derived MSCs is routine,
and its safety and feasibility are confirmed in plenty of
studies. However, using new sources of stem cells with
more therapeutic capability is encouraging. Fortunately,
the presence of a multipotent MSCs population residing
in human glomeruli has been reported (24). During injury,
these cells can differentiate into myofibroblasts which
form the cellular basis of tissue repair. It seems that
tissue-specific stem cells retained superiority in lineage-
specific differentiation along with their resident tissue
origin and natural functions.
Recently, MSCs derived from fetal kidney (fKSCs) was
reported (103,104). These cells express mesenchymal and
renal progenitor markers. They have the ability to differ-
entiate into renal epithelial cells that are commonly
injured during kidney failure. Application of fKSCs results
in rapid restoration of renal function and histology. It up-
regulates the angiogenic proteins such as hypoxia induc-
ible factor 1 (HIF-1a), VEGF and endothelial nitric oxide
synthase (eNOS) that further induce angiogenesis. There-
fore, studies on fKSCs-mediated renal angiogenesis and
regeneration may lead to the development of novel phar-
macological therapies in kidney diseases (104).
MSCs pretreatment with several factors such as
growth factors and vitamins is a novel strategy to
enhance the MSCs efficiency in kidney regeneration. Pre-
treatment with vitamins, such as vitamin E could be ex-
ploited as a new therapeutic approach in regenerative
medicine (63).
Application of natural polymers such as biological scaf-
folds that carry MSCs for tissue repair is another new strat-
egy to increase their efficiency. These scaffolds include
alginate, collagen, fibrin, albumin, hyaluronan, platelet-
rich plasma and gelatin. They are constructs with a fully
vascularized implant that can adapt to the hypoxic environ-
ment in vivo (105,106).
Overall MSCs-based cell therapy would be considered
as a new horizon for the treatment of kidney disease. How-
ever, it must be noted that it is still at the preliminary stages
of development. Further studies including more clinical tri-
als are required in order to achieve the routine application
of MSCs as a new modality for the treatment of kidney in-
juries. We still have to strengthen our knowledge and be
patient.
144 Roushandeh et al./ Archives of Medical Research 48 (2017) 133e146
Acknowledgments
This study was supported by the Iran National Science Foundation
(INSF) (grand no: 91004674).
Conflict of Interest: The authors declare no conflict of interest.
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