Journal of Life Science and Biomedicine  
J Life Sci Biomed, 9 (2): 52-63, 2019  
License: CC BY 4.0  
ISSN 2251-9939  
Current status of stem cell therapy  
Mastewal Birhan1, Amebaye Kenubih2, and Muluken Yayeh3  
Department of veterinary Paraclinical studies, College of Veterinary Medicine and Animal Sciences, University of Gondar, Gondar, Ethiopia  
Corresponding author’s Email:; ORCID: 0000-0002-0984-5582  
PII: S225199391900009-9  
Introduction. Stem cells have the extraordinary potential to develop into many diverse cell  
types in the body during early life and growth. Significant progress has been made in  
understanding the biochemical and metabolic mechanisms and feedback associated with  
different stem cells response. Some of the challenges concerning transplanted embryonic  
stem cells and mesenchymal stem cells are immune-mediated rejection, senescence-induced  
genetic instability or loss of function, and limited cell survival.  
16 August 2018  
15 February 2019  
25 March 2019  
Aim. The aim of this review, is to recapitulate the recent status and information about the  
use of embryonic stem cells and mesenchymal stem cells for research into how cells and  
tissues of the body grow and develop, and potentially useful for curing disease.  
Results. Stem cell therapy efforts are currently underway for virtually every type of tissue  
and organ within the human body. Because the current status of stem cell incorporates the  
fields of cell transplantation, materials science, and engineering, personnel who have  
mastered the techniques of cell harvest, culture, expansion, transplantation, and polymer  
design are essential for the successful application of this technology. Various stem cell  
therapies are at different stages of development, with some already being used clinically, a  
few in preclinical trials, and some in the discovery stage.  
Recommendations. Recent progresses suggest that stem cell therapy may have expanded  
clinical applicability in the future because they represent a viable therapeutic option for  
those who require tissue and cells replacement in diverse degenerative disease. More  
recently, major advances in the areas of stem cell biology, tissue engineering, and nuclear  
transfer techniques have made it possible to combine these technologies to create the  
comprehensive scientific field of regenerative medicine. “But there is a strong need for  
better understanding the biology, manipulation and safety of stem cells in tissue  
regeneration and repair before starting the therapeutic applications.”  
Embryonic Stem Cell,  
Mesenchymal Stem Cell,  
Modern treatments for numerous degenerative diseases like Alzheimer disease, Parkinson disease, motor  
neuron disease, multiple sclerosis, diabetes, and kidney, liver, and heart diseases, as well as for several types of  
cancer, are mostly symptomatic, and for certain diseases, total recovery implies entire organ transplantation [1,  
2]. Numerous applications of stem cells in tried and validated therapies are recognized in humans: starting from  
bone marrow transplants to more recent advances in skin and cornea repair [3]. Stem cell transplantation  
would probably have to be achieved within the window of time between the first appearance of injury and  
irreparable loss of neurons [4].  
Up to date advancement shows that stem cell therapy that concerns cell reprogramming and  
transplantation of Embryonic Stem Cells (ESCs), Mesenchymal Stem Cells (MSCs) and induced pluripotent  
stem cells (iPSCs) represents an interesting so far disputed research area, with exciting results for many  
diseases [3, 5, 6]. Human iPS cell derivation previously required vectors that integrate into the genome, which  
can create mutations and limit the utility of the cells in both research and clinical applications [7].  
The use of stem cells in the clinical field has gathered unbelievable momentum over the last decade,  
advanced by varying levels of achievement in clinical trials and by the advancement in our understanding of the  
mechanisms by which stem cells exert their seemingly favorable effects. Generally speaking, stem cells can be  
characterized as either embryonic or adult stem cells [8]. Stem and progenitor cells from adult tissues represent  
an important promise in the therapy of a number of pathological conditions [9].  
Stem cell transplantation is being widely investigated as a potential therapy for cell death-related heart  
diseases [10]. This rapid translation into clinical studies has left a lot of questions concerning cell therapy  
To cite this paper: Birhan M, Kinubeh A, and Yayeh M. 2019. Current status of stem cell therapy. J. Life Sci. Biomed. 9(2): 52-63;  
unanswered [11, 12]. There is rising evidence that stem cells secrete a variety of growth factors, cytokines,  
chemokines and bioactive lipids that control their biology in an autocrine or paracrine-manner and  
orchestrate interactions with the surrounding microenvironment [13].  
The 21st century is witnessing an uprising in cellular therapy. Stem cell technology is proving to be a  
valuable tool not only for the development and regeneration of various tissue and organ systems, but also as a  
unit in evolution by natural selection [14]. Recently stem cell therapies are assumed to be used as safe and  
effective treatments. Even applications of stem cells are being investigated in clinical trials, including the use of  
stem cells to regenerate damaged tissues such as heart, skin, bone, spinal cord, liver, pancreas and cornea or to  
treat blood or solid-organ cancers [15].  
So that stem cell research is a new field that is advancing at a hard to believe pace with new discoveries  
being reported from all over the world. Scientists have for years looked for ways to use stem cells to replace  
cells and tissues that are damaged or diseased. The miracles of stem cell application in incurable clinical  
conditions are being reported through media and newspapers [16]. To date, stem cell types which have been  
used in clinical trials include hematopoietic stem cells (HSCs), mesenchymal stem cells, neural stem cells,  
epidermal stem cells, endothelial progenitor cells, limbal stem cells, embryonic stem cells, and induced  
pluripotent stem cells [17]. The main properties that characterize stem cells include their indefinite capacity to  
renew themselves and leave their initial undifferentiated state to become cells of several lineages [18].  
Heart failure (HF) is a leading cause of disability and death that accounts for approximately one million  
hospitalizations, over 50,000 deaths, and almost $35 billion in health care costs in the United States each year  
[19]. The use of stem cells in cardiology is frequently characterized as a matter of providing new myocytes, but  
it is much more complex than that. Whether global or segmental, heart failure is generally due to a specific  
cause, which must be removed as a precondition for the success of any reconstructive effort. Likewise, the mere  
generation of new vessels (by means of angiogenesis or vasculogenesis) [20]. Even more important, unlike the  
progenitor cells used in bone marrow transplants, the elementary myocardial functional units are not lone  
cardiomyocytes but, rather, are myocardial cells that are integrated into a multicellular assembly of myofibers.  
These cells are oriented in specific directions (indeed, implanted cell therapy should avoid generating myofiber  
disarray, which is a disease state in itself). Therefore, the challenges of stem cell treatment for the heart are  
much more complex than those of blood transfusion for anemia and bone marrow transplantation for bone  
marrow failure, which is the only clinically successful cellular treatments thus far [19].  
Heart transplantation remains the ultimate approach to treating heart failure, but this is costly and  
excludes patients who are poor candidates for transplantation given their co-morbidities, or for whom a donor  
organ is unavailable. Stem cell therapy represents the first realistic strategy for reversing the effects of what  
has until now been considered terminal heart damage [21]. Therefore, in this review, We attempted to  
summarize the current status, available evidence, and present several clinical and nonclinical data concerning  
mainly the use of ESCs and MSCs in the treatment of dierent cardiovascular disease, highlighting both the  
opportunities and the limitations of stem cell therapy.  
Embryonic Stem Cell  
Since human embryonic stem cell (HESC) lines were first derived in 1998, these cells have been in high  
demand as objects of research. The ability of HESCs to reproduce almost limitlessly and to differentiate into  
many, if not all, cell types of the human body have generated an enormous amount of scientific interest. These  
unique capabilities provide a means of exploring many promising lines of research, which are likely to reveal a  
deeper understanding of human cellular biology and which may lead to potential cures for many diseases  
[22]. Embryonic stem (ES) cells are derived from totipotent cells of the early mammalian embryo and are  
capable of unlimited, undifferentiated proliferation in vitro. The term “ES cell” was introduced to distinguish  
these embryo-derived pluripotent cells from terato-carcinoma-derived pluripotent embryonal carcinoma (EC)  
cells [6].  
Derivation of human embryonic stem cell (HESC)  
HESC lines are conventionally derived from the inner cell mass (ICM) of pre-implantation stage  
blastocysts, of both good and poor quality, which have been donated for research and would otherwise be  
discarded. Morula-stage embryos or late-stage blastocysts (7-8 days) may also be used to create HESC lines.  
Although all the HESC lines derived worldwide share the expression of characteristic pluripotency markers  
To cite this paper: Birhan M, Kinubeh A, and Yayeh M. 2019. Current status of stem cell therapy. J. Life Sci. Biomed. 9(2): 52-63;  
[23]. Many differences are emerging between lines that may be more associated with the wide range of culture  
conditions in current use than with the inherent genetic variations of the embryos from which HESC were  
derived [24].  
Figure 1. Derivation of HESC (human embryonic stem cell) [25].  
Colonies of HESCs differ from the ICM in a number of ways. Firstly, ICM cells retain a memory for axes,  
dorsal-ventral, anterior-posterior, and left-right axes, that enables the differentiating cells to have position  
relationships that guide the differentiation, expansion, and integration of cell types required to form an  
organism. It is generally considered that ESCs are an epiblast derivative, or even a type of germ stem cell, that  
can be maintained as an immortal and pluripotential cell type under strict laboratory conditions, in the  
presence of secretory products of embryonic, or adult, somatic cells. Importantly, the self-renewal of HESCs  
appears to involve the Wnt family signaling pathway and probably other pathways that involve basic fibroblast  
growth factor (bFGF) and TGF-β [23].  
In 1998, Thomson et al. [6] were as a first reporter of the successful derivation of HESCs from  
preimplantation human embryos. Their report followed they extensive studies by Thomson et al. [26] on the  
production of rhesus and marmoset ESCs. Intact blastocysts and mechanically isolated ICMs grown on mouse  
embryonic fibroblasts (STO cells) they are studied by the research group in Singapore from 19941996, and  
these cultures resulted in cell lines that differentiated after several passages in vitro [27].  
The methods finally used successfully to establish HESC lines were described by Reubinoff et al. [28].  
These methods were similar to those described by Thomson et al. [6, 29] and involved the isolation of ICM  
clusters from human blastocysts by immunosurgery and their co-culture with mitotically inactivated murine  
embryonic fibroblasts (MEFs). The HESCs form typical colonies of undifferentiated cells that need to be  
passaged weekly likely or, more often, as mechanically dissected colonies of 10 cells or more. Additional HESC  
lines have been derived by similar methods. More recently HESCs have also been derived under feeder-free  
conditions using cell-free lysates of MEFs [30].  
The selection criteria used for choosing human embryos for deriving HESCs will determine the eventual  
success rates for their production. Small numbers of blastocyst-stage embryos grown in co-culture with human  
oviductal epithelial cells they are used by Reubinoff et al. [28] to produce six HESC lines after preliminary  
experiments involving around 30 embryos [23]. The six HESC lines they are derived from 12 blastocysts. This  
very high success rate of producing HESCs can be compared with the use of much larger numbers of embryos  
(blastocysts) by others. It is probable that about 50% of human embryos have chromosomal abnormalities, and  
it would be expected that these genetic errors would limit the success rate of HESC production. It is also  
difficult to establish HESCs from monosomic or trisomic embryos, with less than 10% made from human  
To cite this paper: Birhan M, Kinubeh A, and Yayeh M. 2019. Current status of stem cell therapy. J. Life Sci. Biomed. 9(2): 52-63;  
embryos diagnosed as aneuploid. Interestingly, two HESC lines produced from trisomic embryos reverted to  
diploidy, indicating the embryos they are probably mosaic [31].  
A large number of HESC lines have been produced from excess human IVF embryos by some IVF clinics;  
for example, Kukharenko et al. [32] reported 46 new HESC lines made from morulae, blastocysts, and ICMs  
isolated from blastocysts [33]. There was apparently little difference between stages of preimplantation human  
embryos in their capacity to form HESC lines. A more recent comparison of mechanical isolation of ICMs and  
plating whole blastocysts for deriving new HESC lines showed that mechanical isolation is more efficient. The  
use of antiserum raised in animals for immunosurgery to isolate ICMs is undesirable [34].  
Genetic manipulation of human embryonic stem cell (HESCs)  
Clonal derivation of HESCs is difficult, and the efficiency is extremely low [35]. However, it is possible to  
transfect HESCs with DNA constructs, and this is important for determining the role of transcription factors  
for the renewal and differentiation of HESCs. Identification of specific gene expression by reporter genes  
enables purification of cells of interest in differentiating cultures and the tracking of HESC derivatives in mixed  
cell cultures or when transplanted into animal models. Conventional transfection methods have been successful  
[36], as have lentiviral methods. Integration of reporter genes into controlling elements of specific genes or the  
approach of gene knock out or knock in used for functional genomics is very difficult because of the inability to  
clone HESCs. However, Zwaka and Thomson [37] have shown that it is possible to electroporate HESCs to  
achieve homologous recombination of HESC colony fragments. Gene function may be more appropriately  
determined in HESCs by using small inhibitory RNAs [38] to control renewal, differentiation, apoptosis and  
other mechanisms involved in cell function and response to internal and external stimuli.  
Markers of human embryonic stem cell (HESCs)  
Sperger et al. [39] have reported that, by microarray analysis, 330 genes are highly expressed in common in  
HESCs and human embryonal carcinoma cells and seminomas. This included POU5F1 (Oct4) and FLJ10713, a  
homolog highly expressed in mESCs. Among those genes only highly expressed in HESCs and human  
embryonal carcinoma cells included a DNA methylase (DNMT3B), which functions in early embryogenesis,  
and Foxd3, a fork head family transcription factor that interacts with Oct4, which is essential for the  
maintenance of mouse primitive ectoderm [40]. Sox2 is also highly expressed and is known to be important in  
pluripotentiality for example: The derivation of neural progenitor cells from human embryonic stem (ES) cells is  
of value both in the study of early human neurogenesis and in the creation of an unlimited source of donor cells  
for neural transplantation therapy. Here we report the generation of enriched and expandable preparations of  
proliferating neural progenitors from human ES cells. The neural progenitors could differentiate in vitro into  
the three neural lineages-astrocytes, oligodendrocytes, and mature neurons. When human neural progenitors  
were transplanted into the ventricles of newborn mouse brains, they incorporated in large numbers into the  
host brain parenchyma, demonstrated widespread distribution, and differentiated into progeny of the three  
neural lineages [41]. Embryonic stem (ES) cells are cells derived from the early embryo that can be propagated  
indefinitely in the primitive undifferentiated state while remaining pluripotent; they share these properties  
with embryonic germ (EG) cells. Serial analysis of gene expression (SAGE) has been reported by Richards et al.  
[42] and has been compare with some cancer SAGE libraries. As expected, Oct4, Nanog, and Sox2 transcripts  
appear abundantly, but there were differences between HESCs in some other transcript abundance (e.g., Rex-1).  
Patient-Specific Stem Cells  
There is much interest in the production of patient-specific stem cells using nuclear transfer techniques to  
introduce somatic cell nuclei into enucleated oocytes [23]. The reason for making HESCs for individual patients  
is for the possible establishment of immune-compatible cell derivatives for transplantation. It is important that  
new disease-specific stem cells be derived from patients with cancers; neurodegenerative diseases such as  
Parkinson’s disease, Alzheimer’s disease, motor neuron disease, and multiple sclerosis; and others of unknown  
cause or multigenic origins. The ability to reestablish pristine HESCs that can be differentiated in the  
laboratory to cells that will express the disease phenotype could be a very valuable resource for screening for  
molecules that interfere with the disease phenotype and identifying candidate drugs or molecular pathways  
that may enable a whole new approach to pharmaceuticals for these patients. This approach has already proven  
productive using mESCs [43].  
To cite this paper: Birhan M, Kinubeh A, and Yayeh M. 2019. Current status of stem cell therapy. J. Life Sci. Biomed. 9(2): 52-63;  
Mesenchymal Stem Cells (MSCs)  
Several progenitor cells can be found in human adult bone marrow. One class of multipotent adult  
progenitors is referred to as mesenchymal stem cells (MSCs). It is well documented that these cells are capable  
of differentiating into bone, cartilage, muscle, marrow stroma, tendon and ligament, fat, and a variety of other  
connective tissue [44]. Like the hematopoietic stem cells (HSCs) of marrow, the differentiation of MSCs involves  
multi-step cell lineages controlled by bioactive factors found in the local micro-environment or supplied in the  
culture environment of ex vivo cultivated cells. This controlled differentiation scheme was evolutionarily  
selected because it comprises a sequential process that can be modulated both in time and end-stage outcome; a  
multi-step pathway allows a large number of regulatory elements to be used to safeguard the final outcome  
[45]. Mesenchymal stem cells (MSCs), also referred to as connective tissue progenitor cells or multipotent  
mesenchymal stromal cells, have demonstrated significant potential for clinical use. Thus, MSCs have been the  
focus of a regime of emerging therapeutics to regenerate damaged tissue and treat inflammation resulting  
from cardiovascular disease and myocardial infarction (MI), brain and spinal cord injury, cartilage and bone  
injury, Crohn's disease, and graft-versus-host disease (GVHD) during bone marrow transplantation [46].  
As part of the minimal criteria, human MSCs must adhere to tissue culture plastic; be positive for CD105,  
CD73, and CD90 and negative for CD45, CD34, CD14 or CD11b, CD79a, or CD19 and HLA-DR; and must be able to  
differentiate to osteoblasts, adipocytes, and chondroblasts under standard in vitro differentiating conditions  
Tissue sources of Mesenchymal Stem Cells (MSC)  
The reported MSC frequency (as measured by CFU-F) and native concentration from several adult human  
tissues are reported. The relative abundance of MSCs throughout the body is understandable in light of recent  
findings that most, if not all, MSCs are of perivascular origin. Furthermore, there is a direct correlation between  
MSC frequency and blood vessel density in stromal vascularized tissue [48]. MSCs and pericytes share the  
phenotypic surface markers melanoma cell adhesion molecule (CD146) and platelet-derived growth factor  
receptor. It is hypothesized that pericytes are the in vivo source of MSCs, with cellular components protruding  
into the endothelial lumen of blood vessels to monitor and react to systemic signals. The widespread  
distribution of perivascular precursors for MSCs would account for their ability to respond to injury by sensing  
and secreting chemokines locally in response to injury, infection or disease in all vascularized tissues of the  
Capacity of Mesenchymal Stem Cells (MSC)  
Trophic properties of MSC: The primary trophic property of MSCs is the secretion of growth factors and  
other chemokines to induce cell proliferation and angiogenesis. MSCs express mitogenic proteins such as  
transforming growth factor-alpha (TGF-α), TGF-β, hepatocyte growth factor (HGF), epithelial growth factor  
(EGF), basic fibroblast growth factor (FGF-2) and insulin-like growth factor-1 (IGF-1) to increase fibroblast,  
epithelial and endothelial cell division. Vascular endothelial growth factor (VEGF), IGF-1, EGF, and angiopoietin-  
1 are released to recruit endothelial lineage cells and initiate vascularization [50].  
Anti-inflammatory and immunomodulatory properties of MSC: MSCs hold up via paracrine mechanisms  
and change the regenerative environment via anti-inflammatory and immunomodulatory mechanisms. In  
response to inflammatory molecules such as interleukin-1 (IL-1), IL-2, IL-12, tumor necrosis factor-a (TNF-a) and  
interferon-gamma (INF-g), MSCs secrete an array of growth factors and anti-inflammatory proteins with  
complex feedback mechanisms among the many types of immune cells [49]. The key immunomodulatory  
cytokines include prostaglandin 2, TGF-b1, HGF, SDF-1, nitrous oxide, indoleamine 2, 3-dioxygenase, IL-4, IL-6,  
IL-10, IL-1 receptor antagonist and soluble tumor necrosis factor-a receptor. MSCs prevent proliferation and  
function of many inflammatory immune cells, including T cells, natural killer cells, B cells, monocytes,  
macrophages and dendritic cells [51].  
Anti-apoptotic properties of MSC: In a situation where MSCs are administered with the aim of treating  
acute lesions, the first expected effect is the reduction of the extent of cell death, and this is observed in animal  
models of tissue injury and in co-culture experiments. Togel et al. reported that infused MSCs attach to the  
renal micro-vascular circulation and decrease apoptosis of adjacent cells in a model of acute kidney injury. In  
To cite this paper: Birhan M, Kinubeh A, and Yayeh M. 2019. Current status of stem cell therapy. J. Life Sci. Biomed. 9(2): 52-63;  
order to elucidate the factors responsible for the observed renoprotective effect, these authors analyzed the  
MSC-conditioned medium and verified the presence of vascular endothelial growth factor (VEGF), hepatocyte  
growth factor (HGF) and insulin-like growth factor 1 (IGF-1), factors that enhance endothelial cell growth and  
survival [48]. Parekkadan et al. [52] found the presence of these and other anti-apoptotic molecules in MSC-  
conditioned medium and, interestingly, showed that an MSC-containing bioreactor connected to the  
bloodstream of rats experimentally subjected to fulminant hepatic failure resulted in the survival of 71% of the  
animals in contrast to 14% survival in the control group.  
MSCs reduce apoptosis of UV-irradiated fibroblasts and lung epithelial tumor cells cultured under low pH  
and hypoxia, and the up-regulation and secretion of stanniocalcin-1 has been found to be at least partially  
responsible for this anti-apoptotic effect [53]. Also, adipose tissue-derived MSCs have been shown to express  
HGF, VEGF, transforming growth factor beta (TGF-β), basic fibroblast growth factor (bFGF, aka FGF2) and  
granulocytemacrophage colony-stimulating factor (GM-CSF), and the expression of these molecules was found  
to increase under hypoxic culture conditions; particularly, VEGF upregulation under hypoxia has been shown to  
be greater than that observed for other factors [54].  
Hypoxia takes place in the first stages of tissue injury, and secretion of anti-apoptotic factors by MSCs at  
this stage minimizes the extent of cell death in the tissues surrounding the injured areas; accordingly, in the  
latter study, it was further demonstrated that cultured, adipose-derived MSCs reduce necrosis and improve  
perfusion when injected into mice experimentally subjected to hind limb ischemia. Scientist’s suggest that this  
anti-apoptotic activity could serve to limit the field of injury in vivo circumstances [54].  
Table 1. Anti-inflammatory mechanisms of MSCs  
Target Cell  
Primery Effect  
↓TNF-ƌ IL-12.  
differentiation and  
Secondary Effect  
↓Impairs effect on  
resting NK cells  
Dendritic cells  
PGE2/direct contact  
PGE2, IL-6. IL-8 and  
SDF-1 PGE2  
Immature Dendritic cells  
↓T.ceII proliferation  
↓INF--, byTH1 cells’  
↓rIL-4 by 1H2 ceilsa  
↓ Treg production.  
IL-10 by Treg cells  
T cells (CD4 +, helper T cells)  
↓CD4 + T-cell  
proliferation by  
↓S-phase entry block  
↓Go/G1 phase arrest  
↓Inhibits T-ceIl  
T cells (CD8 +, Cytotoxic T-  
cells) Treg cells  
↓B-cell proliferation  
↓InactivateTH1- cells  
↓Ig antibody production  
↓by B cells  
↑Treg Proliferation  
PGE2. TGF- β 1, TGF-1,  
IDO. NO and PD-L1  
PGE2. IDO. HLA.G5.  
HGF. TGF- β 1  
↑IL-10 by Treg cells  
↓Trq differentiation  
↓TNF-X and IL-1  
Abbreviations: HGF, hepatocyte growth factor; HLA, human leukocyte antigen; IDO, indoleamine 2,3-dioxygenase; IL-1Ra, IL-1 receptor  
antagonist; INF, interferon; MMP, matrix metalloproteinase; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cell; NK,  
natural killer; NO, nitrous oxide; PD-L1, programmed cell death ligand-1; PGE2, prostaglandin 2; SDF-1, stromal cell-derived factor-1; sTNF-  
R, soluble TNF-a receptor; TGF, transforming growth factor; TNF, tumor necrosis factor; TSG, tumor necrosis alpha-stimulating gene;  
VEGF, vascular endothelial growth factor. A Promotes TH1-TH2 T-cell transition [46].  
Antimicrobial properties of MSC: Assessment of direct inhibition of bacterial growth by MSCs or its  
conditioned medium (CM) was done by counting CFU. In brief, MSCs in 24-theyll plates (2 × 105 cells per well) in  
RPMI supplemented with 5% FBS were infected with 300 CFU E. coli or S. aureus and incubated for 6 hours in  
humidified CO2 incubator, then aliquots of culture medium were taken from each well, serially diluted with  
To cite this paper: Birhan M, Kinubeh A, and Yayeh M. 2019. Current status of stem cell therapy. J. Life Sci. Biomed. 9(2): 52-63;  
sterile PBS, and plated on LB-agar plates (Teknova, Hollister, CA). Colonies were counted after overnight  
incubation at 37°C. Antimicrobial activity of MSC CM (or synthetic LL-37) was tested by a Microdilution  
susceptibility test according to Andra et al. [55].  
The researcher that studied human MSCs might express direct antimicrobial activity through the  
secretion of antimicrobial peptides. They examined the effect of human MSCs on bacterial growth in vitro.  
Expression of different antimicrobial peptides was investigated using reverse transcription polymerase chain  
reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and immuno-histochemistry. Following  
stimulation with live E. coli, human MSCs produced one candidate antimicrobial peptide, LL-37, which was  
subsequently found to be responsible for antimicrobial activity in vitro. To determine if the secretion of LL-37  
by MSCs would alter bacterial clearance in vivo, they tested BM-derived human MSCs in an E. coli pneumonia  
model in mice. Treatment with human MSCs, given 4 hours later, resulted in a significant reduction  
of E.coli colony-forming unit (CFU) in the lung homogenates (LHs) and the bronchoalveolar lavage (BAL) fluids.  
The effect was blocked with a neutralizing antibody to LL-37 demonstrating that human MSCs possessed  
antimicrobial activity, which is explained in part by the secretion of LL-37 [56].  
Phenotypic characterization of Mesenchymal Stem Cells (MSC): After the discovery and early  
characterization of MSCs, scientists desired a method to prospectively isolate progenitor cells from bulk  
populations based upon positive or negative selection of CD markers expressed by the cells. The first markers  
unquestionably identified on MSCs were CD73 (SH-3/4) and CD105 (endoglin or SH-2), followed thereafter by  
CD90 (Thy- 1) and CD44. It since has been discovered that the quadruple-positive population of  
CD90þ/CD105þ/CD73þ/CD44 [57, 58]. It is common to fibroblasts and stromal cells, and only serves to  
discriminate these cell types from those of hematopoietic origin. Significant MSC phenotypic characterization  
has been published in the interim, but unfortunately there remains no strict consensus among the field [59]. In  
2006, the International Society of Stem Cell Research established a minimum set of criteria for defining MSCs  
as: (1) plastic-adherent cells; (2) capable of tri-lineage (bone, cartilage and fat) differentiation; (3)  
phenotypically positive for CD105, CD73 and CD90; and (4) negative for CD45, CD34, CD11b, CD14, CD79a  
and HLA-DR [60]. However, these criteria are based on the characterization of in vitro cultured cells and do  
not apply to the native in vivo phenotype. For example, CD34 is considered a marker for hematopoietic stem  
cells and endothelial progenitors for freshly harvested cells in BM aspirate, but not MSCs [61].  
Pericytes are stimulated by soluble growth factors and chemokines to become activated MSCs, which  
respond to the microenvironment by secreting trophic (mitogenic, angiogenic, anti-apoptotic or scar  
reduction), immunomodulatory or antimicrobial factors. After the microenvironment is re-established,  
MSCs return to their native pericyte state attached to blood vessels [55].  
Figure 2. Phenotypic characterization of MSC.  
To cite this paper: Birhan M, Kinubeh A, and Yayeh M. 2019. Current status of stem cell therapy. J. Life Sci. Biomed. 9(2): 52-63;  
Mesenchymal stem cells (MSC) in the treatment in cardiovascular therapies  
Cardiac: Myocardial infarction is a multi-faceted insult to the cardiovascular system, stemming from  
the initial ischemic event; the extent of damage and subsequent cardiac disease correlates with the size of  
the original infarcted region [62, 63]. It is characterized by the disruption of blood supply to the heart muscle  
cells, which lead to myocardial infarction or death of cardiomyocytes. Reperfusion therapy or the restoration of  
blood flow by thrombolytic therapy, bypass surgery or percutaneous coronary intervention (PCI) is currently  
the mainstay of treatment for AMI and is responsible for the significant reduction in AMI mortalit. The efficacy  
of reperfusion therapy has led to increased survival of patients with severe AMI who would not otherwise  
survive. However, many (23%) of these survivors progress to fatal heart failure within 30 days. This  
phenomenon of an increasing number of severe AMI survivors contributes to an ever growing epidemic of heart  
failures [64].  
Frantz et al. [63] have proposed the possibility of anti-inflammatory agents for minimization of deleterious  
post-myocardial infarction tissue remodeling. Several clinical studies have recently investigated the use of  
MSCs for this purpose; however, there has been no consensus yet on the preferred delivery method or type of  
cell. In a randomized, placebo-controlled study of chronic myocardial infarction patients receiving intra-  
myocardial injections of autologous BM-derived mononuclear cells, cell therapy patients had a decrease in  
summed stress score and increase in left-ventricular (LV) ejection fraction at 3 and 6 months (both statistically  
significant) [65, 66]. A subsequent study of 87 patients with severe LV dysfunction revealed no statistical  
differences in LV ejection fraction or size of infarct between placebo and autologous BMNC infusion [67]. A  
much smaller study revealed that both autologous BM MNCs and expanded BM MSCs yielded a decrease in  
myocardial scarring by 3 months, indicating beneficial tissue remodeling [68].  
Similarly, the percutaneous stem cell injection delivery effects on neomyogenesis (POSEIDON)  
randomized trial comparing allogeneic and autologous MSCs in 30 ischemic cardiomyopathy patients indicated  
increased functional capacity, quality-of-life and ventricular remodeling as a result of both allogeneic and  
autologous cell therapy [69]. Most recently, direct myocardial injection of autologous, expanded BM MSCs  
resulted in persistent improvements in exercise capacity, Canadian cardiovascular scale (CCS) class score,  
angina attack frequency and nitroglycerin consumption at one-year post-intervention [70].  
Opportunities and limitations of stem cell therapy  
One of the limitations of applying cell-based regenerative medicine techniques toward organ replacement  
has been the inherent difficulty of growing specific cell types in large quantities [2]. Another obstacle that  
remains to be fully elucidated is the potential immune response to an ES and MSCs cell derived tissue graft and  
immune-mediated rejection, senescence-induced genetic instability or loss of function, and limited cell survival.  
This is demonstrated by the fact that nude mice, which lack T cells, are unable to mount a rejection response  
against an allogeneic skin graft. The unique ability of ES cells to give rise to HSC offers an interesting potential  
whereby immunological tolerance can be induced via hematopoietic chimerism [71].  
Build out of regenerative service lines is predicated on effective clinical-grade biotherapies suitable for  
scale-up and standardized production and application. A viable supply chain requires quality-controlled  
manufacturing and delivery of products that fulfill patient specifications. Patient modifiers such as age, sex,  
morbidities, and concomitant therapies impact regenerative fitness. Cell performance is also subject to  
influences during procurement, production, and/or delivery. In fact, not all individuals harbor stem cells with a  
uniform reparative capacity [72].  
The past decade has improved our knowledge of stem cell biology and the development of the cardiovascular  
system. However, a more profound understanding of cardiac myogenesis will be required for the development  
of advanced stem cell therapeutics to repair or regenerate damaged money disease [73]. The future will likely  
include (i) further investigation to delineate the human CM lineage tree; (ii) methods to isolate specifc cardiac  
progenitor pools or specialized CM subtypes; (iii) strategies to ensure survival of transplanted cells, their  
functional integration with the host myocardium, and circumvention of immune rejection; (iv) development of  
technologies to accurately assess integration; (v) determination of parameters that optimize engraftment, such  
To cite this paper: Birhan M, Kinubeh A, and Yayeh M. 2019. Current status of stem cell therapy. J. Life Sci. Biomed. 9(2): 52-63;  
as delivery method, timing of transplantation post-MI, and cell preparations; and (vi) large-animal models of  
heart failure that closely resemble human cardiovascular physiology and disease for assessing cell engraftment,  
host immune response, and myocardial function [74].  
Cell-replacement therapies hold great potential for treating Alzheimer’s disease and related disorders  
patients. With the advent of stem cell technologies and the ability to turn stem cells into different types of  
CNS neurons and glial cells, some success in stem cell therapy has been made in animal models of  
Alzheimer’s disease. Although these preclinical studies are promising, many more steps remain before stem  
cell therapies can be successfully used for the treatment of Alzheimer’s disease and related disorders [75].  
Stem cells therapy is under investigation for a number of therapeutic applications. These cells are known to  
home to some tissues, particularly when injured or under pathological conditions. The mechanisms underlying  
migration of MSCs and ESCs remain to be clarified, although evidence suggests that both chemokines and their  
receptors and adhesion molecules are involved. Different studies describe the role of chemokine receptors and  
adhesion molecules on stem cells may allow the development of therapeutic strategies to enhance the  
recruitment of ex vivo-cultured MSCs to damaged or diseased tissues. This could lead to various therapeutic  
possibilities such as supporting tissue regeneration, correcting inherited disorders (e.g., of bone), dampening  
chronic inflammation, and using these cells as vehicles for the delivery of biological agents. Further clinical data  
are necessary, however, to determine the in vivo distribution and therapeutic mechanisms of MSCs and ESCs to  
optimize their use as part of a personalized regenerative medicine strategy. This process will require the  
collaborative efforts of physicians, veterinarian, scientists, biotechnologiests, industry and regulatory agencies  
to translate nature’s basic regenerative element into the continuum of clinical care. Stem cells are the potiential  
area for research and doing new regenerative engnering and cell therapy at the cell levels.  
Authors' contributions  
MB conceived the review, coordinated the overall activity, and reviewed the manuscript. AK and MY  
supervising all in all activities.  
Availability of data and materials  
Data will be made available upon request of the primary author.  
The authors’ heartfelt thanks will also go to the university of the Gondar for resourse supporting.  
Competing interests  
The authors declare that they have no competing interests.  
Consent to publish  
Not applicable.  
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