stem cell theraby in parasitic diseases

8/10/2019 Stem Cell Theraby in Parasitic Diseases

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Stem cell theraby for some

parasitic diseasesStem cells are undifferentiated biological cells that can differentiate

into specialized cells and can divide (through mitosis) to produce

more stem cells. They are found in multicellular organisms. In

mammals, there are two broad types of stem cells: embryonic stem

cells, which are isolated from the inner cell mass of blastocysts, andadult stem cells, which are found in various tissues. In adult

organisms, stem cells and progenitor cells act as a repair system for

the body, replenishing adult tissues. In a developing embryo, stem

cells can differentiate into all the specialized cellsectoderm,

endoderm and mesoderm but also maintain the normal turnover of

regenerative organs, such as blood, skin, or intestinal tissues.

There are three known accessible sources of autologous adult stem

cells in humans:

1. Bone marrow, which requires extraction by harvesting, that is,

drilling into bone (typically the femur or iliac crest).

2. Adipose tissue (lipid cells), which requires extraction by

liposuction.

3. Blood, which requires extraction through apheresis, wherein

blood is drawn from the donor (similar to a blood donation), and


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passed through a machine that extracts the stem cells and returns

other portions of the blood to the donor.

Stem cells can also be taken from umbilical cord blood just after birth.

Of all stem cell types, autologous harvesting involves the least risk. By

definition, autologous cells are obtained from one's own body, just as

one may bank his or her own blood for elective surgical procedures.

Adult stem cells are frequently used in medical therapies, for example

in bone marrow transplantation. Stem cells can now beartificially

grown and transformed (differentiated) into specialized cell types

with characteristics consistent with cells of various tissues such as

muscles or nerves. Embryonic cell lines and autologous embryonic

stem cells generated through Somatic-cell nuclear transfer or

dedifferentiation have also been proposed as promising candidates

for future therapies.

Properties

The classical definition of a stem cell requires that it possess two

properties:

Self-renewal: the ability to go through numerous cycles of cell

division while maintaining the undifferentiated state.

Potency: the capacity to differentiate into specialized cell types.

In the strictest sense, this requires stem cells to be either totipotent

or pluripotentto be able to give rise to any mature cell type,

Potency specifies the differentiation potential (the potential to

differentiate into different cell types) of the stem cell.[4]


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Totipotent (a.k.a. omnipotent) stem cells can differentiate into

embryonic and extraembryonic cell types. Such cells can construct a

complete, viable organism.These cells are produced from the fusion

of an egg and sperm cell. Cells produced by the first few divisions of

the fertilized egg are also totipotent.

Pluripotent stem cells are the descendants of totipotent cells

and can differentiate into nearly all cells, i.e. cells derived from any of

the three germ layers.

Multipotent stem cells can differentiate into a number of cell

types, but only those of a closely related family of cells.

Oligopotent stem cells can differentiate into only a few cell

types, such as lymphoid or myeloid stem cells.

Unipotent cells can produce only one cell type, their own, but

have the property of self-renewal, which distinguishes them from

non-stem cells (e.g. progenitor cells, muscle stem cells).

The patients with parasitic infections, who usually belong to the

lower socioeconomic strata of our society, have limited therapeutic

options. Chemotherapy is virtually the first choice for the treatment

of many parasitic infections. However, there is a worry about drug

resistance following long-term, repeated implementation of mass

drug administration. Stem cell therapy may help these patients.

Stem cell therapy is an interventional treatment that introduces new

cells into damaged tissues, which help in treating many diseases and

injuries. It has been proved that stem cell therapy is effective for the

treatment of cancers, diabetes mellitus, Parkinson's disease,


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Huntington's disease, cardiovascular diseases, neurological disorders,

and many other diseases. Recently, stem cell therapy has been

introduced to treat parasitic infections. The culture supernatant of

mesenchymal stem cells (MSCs) is found to inhibit activation and

proliferation of macrophages induced by the soluble egg antigen of

Schistosoma japonicum, and MSC treatment relieves S. japonicum-

induced liver injury and fibrosis in mouse models. In addition,

transplantation of MSCs into nave mice is able to confer host

resistance against malaria, and MSCs are reported to play an

important role in host protective immune responses against malaria

by modulating regulatory T cells. In mouse models of Chagas disease,

bone marrow mononuclear cell has been shown effective in reducing

inflammation and fibrosis in mice infected with Trypanosoma cruzi,

and transplantation of the bone marrow mononuclear cells prevents

and reverses the right ventricular dilatation induced by T. cruzi

infection in mice. Preliminary clinical trials demonstrate that

transplantation of bone marrow derived-cells may become an

important therapeutic modality in the management of end-stage

heart diseases associated with Chagas disease. Based on these

exciting results, it is considered by stating that it is firmly believed

that, within the next few years, we will be able to find the best animal

models and the appropriate stem cell type, stem cell number,

injection route, and disease state that will result in possible benefits

for the patients with parasitic infections, and stem cell therapy,

although at an initial stage currently, will become a real therapeutic


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option for parasitic diseases.

The 2012 Nobel Prize in Physiology or Medicine was awarded jointly

to John B. Gurdon and Shinya Yamanaka for the discovery that mature

cells can be reprogrammed to become pluripotent. Their surprising

discov- eries have provided new tools for scientists around the world

and led to remarkable progress in many areas of medicine. Actually,

stem cell therapy has generated a huge amount of attention during

the last two decades. Stem cell therapy is a kind of intervention

strategy that introduces new cells into damaged tissues, which help in

treating many diseases and injuries.

Stem cell therapy for schistosomiasis

Schistosomiasis, caused by blood flukes (trematodes) of the genus

Schistosoma, is an infectious disease affecting over 300 million

people and leading to the loss of 1.53 million disability-adjusted life

years in tropical and subtropical areas of the world. The major

pathologic lesions of schistosomiasis are the hepatic granuloma

formation around schistosome eggs at acute stage of the infection,

followed by hepatic fibrosis at chronic and advanced stages.

Currently, the treatment of this neglected tropical disease still

depends on praziquantel, the drug of choice for human

schistosomiases. However, the potential likelihood of emergence of

praziquantel resistance urges the development of novel strategies for

the treatment of Schistosoma japonicum infections


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Mesenchymal stem cells (MSCs), which have potential as seed cells,

can be used for the treatment of various human diseases, including

pathogenic infections. Considering the previous successes in therapy

of infectious diseases and their antifibrotic effects, MSC therapy was

introduced with the aim to evaluate the potential of MSCs for treating

S. japonicum infections. It was observed that the RAW264.7 mouse

macrophages be- came round, with significantly reduced sizes and

less pseudo- podia following incubation in the MSC culture

supernatant plus soluble egg antigen (SEA) of S. japonicum for 12 h,

as compared to those cultured in SEA, SEA plus Dulbeccos Modified

Eagle Medium (DMEM), and SEA plus the culture supernatant of the

rat renal tubule epithelial cell line NRK- 52E. The TNF - mRNA levels

in the macrophages cultured in the MSC culture supernatant plus SEA

for 12 and 24 h were 1.0 0.4 and 1.0 0.5 times greater than those

in negative controls, but they were significantly lower than those

cultured in SEA plus NRK-52E cell culture supernatant and SEA plus

DMEM (all P values


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SEA plus DMEM (0.31 0.03, P < 0.05), respectively. These findings

demonstrate that the MSC culture supernatant can inhibit activation

and proliferation of macrophages induced by S. japonicum SEA,

which provides the theoretical evidence for the application of MSCs in

the treatment of hepatic fibrosis associated with S. japonicum

infection .

In mice experimentally infected with S. japonicum, MSC treatment

was found to prolong the survival of infected mice with reduced egg

granuloma diameters and decrease the levels of serum transforming

growth factor-1 and hyaluronic acid. Treatment with MSCs has been

shown to inhibit the collagen deposition and reduce the expression of

collagen type 3, - smooth muscle actin, and vimentin in the liver

tissues of the infected mouse. In addition, MSCs have been reported

to be able to improve the liver injury induced by S. japonicum

infection in vivo and this effect is enhanced by combining MSCs with

praziquantel. These findings suggest that MSC treatment is a novel

therapeutic approach for S. japonicum- induced liver injury and

fibrosis.

Stem cell therapy for malaria

Malaria is the worlds most important parasitic infectious disease,

and the infection begins by the bite of a female Anopheles mosquito

which feeds on human blood. The malaria parasites rapidly infect

human erythrocytes, spleen cells, and hepatocytes, resulting in


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anemia by destruction of these cells and a variable degree of bone

marrow dyserythropoiesis .

Based on the finding that hemoglobin variants protect from malaria,

it is hypothesized that stem cell engineering may yield erythrocytes

with new modified hemoglobin that may protect against severe

malaria. Scientists from the National Institute for Medical Research,

UK have identified an atypical progenitor cells from malaria-infected

mice which can give rise to a lineage of cells capable of fighting this

disease, and transplantation of these cells into mice with severe

malaria helps mice recover from the disease. In addition, multipotent

hemopoietic stem cells were reported to play an important role in the

hosts defense mechanisms against Plasmodium berghei infection. In

mice infected with P. berghei, massive recruitment of MSCs is

observed in secondary lymphoid organs, and transplantation of these

cells into nave mice was able to confer host resistance against

malaria. Furthermore, MSCs are found to increase IL- 12 production

but suppress IL-10 production in recipient animals, and dramatic

reductions of regulatory T cells are detected in animals undergoing

infusion of MSCs. It is there- fore concluded that MSCs play an

important role in host protective immune responses against malaria

by modulating regulatory T cells.

Stem cell therapy for Chagas disease

Chagas disease, a neglected tropical disease caused by the parasite

Trypanosoma cruzi, remains a major public health concern in Latin


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America, and the disease is being spread to developed countries as a

result of the migration of infected individuals. The infection has

recently caught the attention of the medical community outside the

endemic countries, particularly those involved in cardiovascular

medicine and surgery. Typical cardiac manifestations of Chagas

disease include dilated cardiomyopathy, congestive heart failure,

arrhythmias, cardio embolism, and stroke, and chagasic

cardiomyopathy is associated with congestive heart failure which is

often refractory to medical therapy.

In mouse models of Chagas disease, bone marrow mononuclear cell

was found to be effective in reducing inflammation and fibrosis in

mice infected with the protozoan T. cruzi, and transplantation of the

bone marrow mononuclear cells prevented and reversed the right

ventricular dilatation induced in mice by T. cruzi infection. It has been

shown that repeated injections of granulocyte colony-stimulating

factor (G-CSF), which mobi- lizes stem cells from the bone marrow,

decreases inflammation and fibrosis in the hearts of chagasic mice.

While chagasic mice had 1,702 (out of 9,390) cardiac genes with

expression altered by infection, after bone marrow mononuclear cell

therapy, 96 % of these genes were restored to normal levels, although

an additional 109 genes had their expression altered by therapy. To

investigate the migration of transplanted MSCs in a murine model of

Chagas disease, and correlate MSC bio-distribution with glucose

metabolism and morphology of heart in chagasic mice by small

animal positron emission tomography (microPET), mice were


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infected intraperitoneally with trypomastigotes of the Brazil strain of

T. cruzi and treated by tail vein injection with MSCs 1 month after

infection. The in vivo imaging system revealed that a small, but

significant, number of cells migrated to chagasic hearts 2 days post

transplantation as compared to the control animals, whereas a vast

majority of near-infrared fluorescent nanoparticle-labeled MSCs

migrated to liver, lungs, and spleen. Additionally, the microPET

technique demonstrated that therapy with MSCs reduced right

ventricular dilation, a phenotype of the chagasic mouse model. In

Wistar rats, simultaneous autologous transplantation of cocultured

mesenchymal stem cells and skeletal myoblasts was found to

significantly improve ejection fraction (EF) and reduce left

ventricular end- diastolic volume (LVEDV) and left ventricular end-

systolic volume (LVESV), indicating that cotransplant of stem cells

and skeletal myoblasts is functionally effective in the Chagas disease

ventricular dysfunction.

The exciting results in animal experiments urge the trials to test the

feasibility of stem therapy for the treatment of Chagas diseases. In 28

patients with heart failure due to Chagas disease, bone marrow cell

transplantation caused significant improvements in the New York

Heart Association (NYHA) class, quality of life, and distance walked in

6 min, suggesting that intracoronary injection of bone marrow mono-

nuclear cells is feasible and it may be potentially safe and effective in

patients with congestive heart failure due to Chagas disease. Based on

the promising results of the initial trials, a multicenter randomized


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trial was performed to test the efficacy of intracoronary delivery of

bone marrow-derived mononuclear cells in chronic chagasic

cardiomyopathy patients. The subjects aged 18 to 75 years with

chronic chagasic cardiomyopathy, NYHA class II to IV heart failure,

LVEF < 35, and optimized therapy were randomized to intracoronary

injection of autologous bone marrow-derived mononuclear cells

(BMNCs) or placebo. The primary end point was the difference in

LVEF from baseline to 6 and 12 months after treatment between

groups. Following infection of BMNCs at a median number of 2.20

108 (range, 1.403.50 108), the alteration of LVEF did not differ

significantly between the treatment groups: trimmed mean change in

LVEF at 6 months, 3.0 (1.34.8) for BMNCs and 2.5 (0.64.5) for

placebo (P = 0.519); change in LVEF at 12 months, 3.5 (1.55.5) for

BMNCs and 3.7 (1.56.0) for placebo (P = 0.850). The left ventricular

systolic and diastolic volumes, NYHA class, Minnesota quality-of-life

questionnaire, brain natriuretic peptide concentrations, and 6-min

walking test did not also differ between groups. It was concluded that

intracoronary injection of autologous BMNCs does not improve left

ventricular function or quality of life in patients with chronic chagasic

cardiomyopathy. Given the encouraging results obtained from animal

experiments and trials, the further evaluation of the feasibility and

safety of stem cell therapy for the treatment of Chagas diseases

requires increased efforts which are currently ongoing.


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It is considered that combined health effects of multiple con- current

parasite infections are the source, as well as the effect, of poverty. The

patients with parasitic infections, who usually belong to the lower

socioeconomic strata of our society, have limited therapeutic options.

Chemotherapy is virtually the first choice for the treatment of many

parasitic infections. However, there is a worry about drug resistance

following long-term, repeated implementation of mass drug

administration. Stem cell therapy may help these patients, although at

an initial stage currently, and efforts will be continued to make it

become a real therapeutic option for parasitic diseases through the

ability to find the best animal models and the appropriate stem cell

type, stem cell number, injection route, and disease state that will

result in possible benefits for the patients with parasitic infections.

stem cell theraby in parasitic diseases

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