Wharton’s jelly mesenchymal stem cells: Future regenerative medicine for clinical applications in mitigation of radiation injury

Wharton’s jelly mesenchymal stem cells(WJ-MSCs)are gaining significant attention in regenerative medicine for their potential to treat degenerative diseases and mitigate radiation injuries.WJ-MSCs are more naïve and have a better safety profile,making them suitable for both autologous and allogeneic transplantations.This review highlights the regenerative potential of WJ-MSCs and their clinical applications in mitigating various types of radiation injuries.In this review,we will also describe why WJ-MSCs will become one of the most probable stem cells for future regenerative medicine along with a balanced view on their strengths and weaknesses.Finally,the most updated literature related to both preclinical and clinical usage of WJ-MSCs for their potential application in the regeneration of tissues and organs will also be compiled.

Potential plausible role of Wharton’s jelly mesenchymal stem cells for diabetic bone regeneration

This letter addresses the review titled“Wharton’s jelly mesenchymal stem cells:Future regenerative medicine for clinical applications in mitigation of radiation injury”.The review highlights the regenerative potential of Wharton’s jelly mesenchymal stem cells(WJ-MSCs)and describes why WJ-MSCs will become one of the most probable stem cells for future regenerative medicine.The potential plausible role of WJ-MSCs for diabetic bone regeneration should be noticeable,which will provide a new strategy for improving bone regeneration under diabetic conditions.

Increasing Incidence of Diabetes Mellitus, Systemic Hypertension and Germ Cells with Endogenous Estrogen

Background: Era of contraception, abortions, [20th, 21st centuries] implemented as family welfare schemes, witnessed increased global incidence of Type 2 diabetes mellitus, systemic hypertension. Objectives: Altruistic association of contraception [if any], with increasing diabetes mellitus, systemic hypertension, was sought after. Methods: In 2012, retrospective analysis of, prevalence of diabetes mellitus, systemic hypertension, in 350 patients of 20 - 35 years, 35 - 50 years, >50 years, age groups, data collected by convenient, stratified random sampling, from different geographical locations, between 2003-2012 and its association with presence, absence of contraception, abortion was undertaken;simultaneously, serum estrogen levels obtained from 105 patients, were also analysed. Results: 10 - 45 fold increase in Type 2 diabetes mellitus was seen in contraceptive users of >20 years to >50 years;15 - 50 fold increase in incidence of systemic hypertension was seen in contraceptive users of >20 years to >50 years. Endogenous estrogen was reduced below normal in 75% of contraceptive users, and 25% of contraceptive users had low normal serum estrogen. Cholesterol deprived diet, due to decreased synthesis of endogenous estrogen, androgen also was associated with 50% increase in diabetes mellitus, systemic hypertension. Conclusion: Concept is acquired contraception, abortion status, with smashed fragmentation of germ cells, reduced endogenous estrogen, androgen, results in defaulted genomic repertoire, deranged cell metabolism, increased incidence of diabetes mellitus, systemic hypertension as part of metabolic syndrome. Contraception reversal declined the diseases as a cause and effective phenomenon.

The therapeutic potential of mesenchymal stem cells in Alzheimer's disease:converging mechanisms

Mesenchymal stem cells （MSCS） are pluripotent stem cells isolated from various tissues, but mostly from bone marrow, adipose tissue, and umbilical cord blood. Well known for their mesenchymal lineages differentiation （e.g., bone, cartilage and fat tissues）, it was suggested that MSCs possess plasticity prop- erties enabling them to differentiate into non-mesenchymal lineages. Indeed, several protocols claimed for differentiating MSCs to neurons in vitro, but concern was raised for the ef- fectiveness and in vivo relevance of such differentiation. Thus, though their neurogenic differentiation properties are still in debate, they were nevertheless, suggested as candidates for treat- ing neurodegenerative disorders such as Parkinson＇s diseases, multiple sclerosis and Alzheimer＇s disease （AD）.

Human Wharton’s jelly mesenchymal stem cells inhibit cytokine storm in acute respiratory distress syndrome in a rat model

Objective:To evaluate the potential effect of human Wharton’s jelly mesenchymal stem cells(hWJMSCs)on acute respiratory distress syndrome in lipopolysaccharide(LPS)-induced rats.Methods:The hWJMSCs(5×10^(4)/mL,5×10^(5)/mL,5×10^(6)/mL)were administered to rats on day 1 and day 8 after being induced by LPS(5 mg/kg body weight).TNF-αlevels in the lung and IL-18 and IL-1βlevels in the serum were measured using ELISA.In addition,caspase-1 expression in lung tissues was quantified using qRT-PCR,and NF-κB and IL-6 expressions were assessed using immunohistochemistry.Results:The hWJMSCs decreased TNF-αlevels in the lung and plasma IL-18 and IL-1βlevels.Moreover,the hWJMSCs downregulated the expressions of caspase-1,IL-6,and NF-κB in lung tissues.Conclusions:The hWJMSCs can decrease inflammatory markers of acute respiratory distress syndrome in a rat model and may be further investigated for the treatment of acute respiratory distress syndrome.

Comparison between the therapeutic effects of differentiated and undifferentiated Wharton’s jelly mesenchymal stem cells in rats with streptozotocin-induced diabetes

BACKGROUND Despite the availability of current therapies,including oral antidiabetic drugs and insulin,for controlling the symptoms caused by high blood glucose,it is difficult to cure diabetes mellitus,especially type 1 diabetes mellitus.AIM Cell therapies using mesenchymal stem cells(MSCs)may be a promising option.However,the therapeutic mechanisms by which MSCs exert their effects,such as whether they can differentiate into insulin-producing cells (IPCs) beforetransplantation, are uncertain.METHODSIn this study, we used three types of differentiation media over 10 d to generateIPCs from human Wharton’s jelly MSCs (hWJ-MSCs). We further transplantedthe undifferentiated hWJ-MSCs and differentiated IPCs derived from them intothe portal vein of rats with streptozotocin-induced diabetes, and recorded thephysiological and pathological changes.RESULTSUsing fluorescent staining and C-peptide enzyme-linked immunoassay, we wereable to successfully induce the differentiation of hWJ-MSCs into IPCs.Transplantation of both IPCs derived from hWJ-MSCs and undifferentiated hWJMSCshad the therapeutic effect of ameliorating blood glucose levels andimproving intraperitoneal glucose tolerance tests. The transplanted IPCs homedto the pancreas and functionally survived for at least 8 wk after transplantation,whereas the undifferentiated hWJ-MSCs were able to improve the insulitis andameliorate the serum inflammatory cytokine in streptozotocin-induced diabeticrats.CONCLUSIONDifferentiated IPCs can significantly improve blood glucose levels in diabetic ratsdue to the continuous secretion of insulin by transplanted cells that survive in theislets of diabetic rats. Transplantation of undifferentiated hWJ-MSCs cansignificantly improve insulitis and re-balance the inflammatory condition indiabetic rats with only a slight improvement in blood glucose levels.

Stem cells and Parkinson's disease

Totally three articles focusing on ＂bone marrow mesenchymal stem cells alleviating PC12 cytotoxicity induced by 6-hydroxydopamine and intracerebroventricular transplantation of non-modified/gene-modified stem cells for treatment of Parkinson＇s disease＂ are published in three issues. We hope that our readers find these papers useful to their research.

Soluble factors secreted by human Wharton’s jelly mesenchymal stromal/stem cells exhibit therapeutic radioprotection: A mechanistic study with integrating network biology

BACKGROUND Human Wharton’s jelly-derived mesenchymal stromal/stem cells(hWJ-MSCs)have gained considerable attention in their applications in cell-based therapy due to several advantages offered by them.Recently,we reported that hWJ-MSCs and their conditioned medium have significant therapeutic radioprotective potential.This finding raised an obvious question to identify unique features of hWJ-MSCs over other sources of stem cells for a better understanding of its radioprotective mechanism.AIM To understand the radioprotective mechanism of soluble factors secreted by hWJMSCs and identification of their unique genes.METHODS Propidium iodide staining,endogenous spleen colony-forming assay,and survival study were carried out for radioprotection studies.Homeostasis-driven proliferation assay was performed for in vivo lymphocyte proliferation.Analysis of RNAseq data was performed to find the unique genes of WJ-MSCs by comparing them with bone marrow mesenchymal stem cells,embryonic stem cells,and human fibroblasts.Gene enrichment analysis and protein-protein interaction network were used for pathway analysis.RESULTS Co-culture of irradiated murine splenic lymphocytes with WJ-MSCs offered significant radioprotection to lymphocytes.WJ-MSC transplantation increased the homeostasis-driven proliferation of the lymphocytes.Neutralization of WJ-MSC conditioned medium with granulocyte-colony stimulating factor antibody abolished therapeutic radioprotection.Transcriptome analysis showed that WJ-MSCs share several common genes with bone marrow MSCs and embryonic stem cells and express high levels of unique genes such as interleukin(IL)1-α,IL1-β,IL-6,CXCL3,CXCL5,CXCL8,CXCL2,CCL2,FLT-1,and IL-33.It was also observed that WJ-MSCs preferentially modulate several cellular pathways and processes that handle the repair and regeneration of damaged tissues compared to stem cells from other sources.Cytokine-based network analysis showed that most of the radiosensitive tissues have a more complex network for the elevated cytokines.CONCLUSION Systemic infusion of WJ-MSC conditioned media will have significant potential for treating accidental radiation exposed victims。

Protective effects of components of the Chinese herb grassleaf sweetflag rhizome on PC12 cells incubated with amyloid-beta42

The major ingredients of grassleaf sweetflag rhizome are β-asarone and eugenol, which can cross the blood-brain barrier and protect neurons. This study aimed to observe the neuroprotective effects and mechanisms of β-asarone and eugenol, components of the Chinese herb grassleaf sweetflag rhizome, on PC12 cells. First, PC12 cells were cultured with different concentrations（between 1 × 10–10 M and 1 × 10–5 M） of β-asarone and eugenol. Survival rates of PC12 cells were not significantly affected. Second, PC12 cells incubated with amyloid-beta42, which reduced cell survival, were cultured under the same conditions（1 × 10–6 M β-asarone and eugenol）. The survival rates of PC12 cells significantly increased, while expression levels of the m RNAs for the pro-apoptotic protein Bax decreased, and those for the anti-apoptotic protein Bcl m RNA increased. In addition, the combination of β-asarone with eugenol achieved better results than either component alone. Our experimental findings indicate that both β-asarone and eugenol protect PC12 cells through inhibiting apoptosis, and that the combination of the two is better than either alone.

IPN's PVA AND ITS CELL GROWTH PROPERTY

6 kinds of IPN's PVA were synthesized by using different monomers of HEMA, MAA and MMA. The effect of adding polysaccharide was also studied. The cell growth on them were determined and compared. The results showed that the cell growth property of the IPN's PVA with hydrophobic monomer of MMA is better, and it can be improved further by adding hyaluronic acid.

Differentiation of Wharton's jelly mesenchymal stem cells into neurons in alginate scaffold

Alginate scaffold has been considered as an appropriate biomaterial for promoting the differentiation of embryonic stem cells toward neuronal cell lineage. We hypothesized that alginate scaffold is suitable for culturing Wharton’s jelly mesenchymal stem cells（WJMSCs） and can promote the differentiation of WJMSCs into neuron-like cells. In this study, we cultured WJMSCs in a three-dimensional scaffold fabricated by 0.25% alginate and 50 m M Ca Cl2 in the presence of neurogenic medium containing 10 μM retinoic acid and 20 ng/m L basic fibroblast growth factor. These cells were also cultured in conventional two-dimensional culture condition in the presence of neurogenic medium as controls. After 10 days, immunofluorescence staining was performed for detecting β-tubulin（marker for WJMSCs-differentiated neuron） and CD271（motor neuron marker）. β-Tubulin and CD271 expression levels were significantly greater in the WJMSCs cultured in the three-dimensional alginate scaffold than in the conventional two-dimensional culture condition. These findings suggest that three-dimensional alginate scaffold cell culture system can induce neuronal differentiation of WJMSCs effectively.

Hidden Hearing Loss: Causes, Current Knowledge, and Future Directions

Introduction: Hidden hearing loss (HHL) is a type of auditory disorder that affects the auditory neural processing and hearing sensitivity in subjects with normal hearing thresholds. Unlike central auditory processing disorders, HHL happens when the cochlea (the peripheral auditory organ) is affected. There are several known risk factors to HHL which includes noise exposure, ototoxic drugs, and peripheral neuropathies, and age. Recent studies have shed light on this type of hearing loss, its etiology, prevalence, and how it can affect the auditory acuity in humans. Methods: This paper covers the current research regarding HHL, its causes, the different mechanisms involved in this disorder, and the diagnosis and potential treatments related to it. We will delve deeply into different researches concerning HHL. 4 articles from 285 were selected focusing on normal hearing individuals with bad speech intelligibility were discussed in this paper. In addition, articles discussing the effects of noise exposure on hearing impaired individuals were not considered as this study solely aims to focus on normal hearing sensitivity individuals with HHL, resulting in 4 articles from 285. Results: Numerous literatures over the decades have suggested that HHL is due to the degeneration of cochlear ribbon synapses, or hair cells synapses without hair cell damage. Their association with HHL was noted several times through this study, whether we were studying the effect of noise exposure, of age, or of ototoxicity. In all cases, no significant hair cell damage was observed, and normal thresholds were recovered. However, a decline in the amplitude of Auditory Brainstem Response (ABR) peak I from auditory nerve (AN) responses in noise exposed subjects and a decline in compound action potential (CAP) was measured when certain drugs were applied to the round window of Guinea pigs. Conclusion: Most studies, have proven that cochlear synaptophysin is the major contributor to noise induced, age, and ototoxic related HHL. There are several audiometric tests that were used to help identify HHL including Puretone audiometry in background noise, ABR, CAP, Distortion Product Otoacoustic Emission (DPOAE).

Presenilin mutations and their impact on neuronal differentiation in Alzheimer’s disease

The presenilin genes(PSEN1 and PSEN2)are mainly responsible for causing early-onset familial Alzheimer’s disease,harboring~300 causative mutations,and representing~90%of all mutations associated with a very aggressive disease form.Presenilin 1 is the catalytic core of theγ-secretase complex that conducts the intramembranous proteolytic excision of multiple transmembrane proteins like the amyloid precursor protein,Notch-1,N-and E-cadherin,LRP,Syndecan,Delta,Jagged,CD44,ErbB4,and Nectin1a.Presenilin 1 plays an essential role in neural progenitor maintenance,neurogenesis,neurite outgrowth,synaptic function,neuronal function,myelination,and plasticity.Therefore,an imbalance caused by mutations in presenilin 1/γ-secretase might cause aberrant signaling,synaptic dysfunction,memory impairment,and increased Aβ42/Aβ40 ratio,contributing to neurodegeneration during the initial stages of Alzheimer’s disease pathogenesis.This review focuses on the neuronal differentiation dysregulation mediated by PSEN1 mutations in Alzheimer’s disease.Furthermore,we emphasize the importance of Alzheimer’s disease-induced pluripotent stem cells models in analyzing PSEN1 mutations implication over the early stages of the Alzheimer’s disease pathogenesis throughout neuronal differentiation impairment.

An Eperimental Study on the Transplantation of Human Fetal Brain Cells into Monkey Models of Parkinson's Disease.

Unilateral administration of methly-phenyl-tetrahydropyridine(MPTP) into the common carotid artery

INTRACEREBRAL CO-GRAFTING OF SCHW ANN'S CELLS AND FETAL ADRENAL MEDULLA IN THE TREATMENT OF PARKINSON'S DISEASE

Intracerebral co-grafting of Schwann's cells and human fetal adrenal medullary tissue was performed in 10 patients with Parkinson's disease. One to six months after grafting, symptoms were improved significantly for 1 to 3 grade. Among them, 2 patients resumed nearly normal daily activities. Long-term follow-up showed that the symptoms were not improved satisfactorily in some patients. It is considered that careful selection of patients, administration of amantadine, and co-grafting of Schwann's cells which prompts the survival of chromaffin cells are essential to better results.

Yeast Two-Hybrid Screening for Proteins that Interact with the Extracellular Domain of Amyloid Precursor Protein

Alzheimer＇s disease（AD） is a neurodegenerative disorder in which amyloid b plaques are a pathological characteristic. Little is known about the physiological functions of amyloid b precursor protein（APP）. Based on its structure as a type I transmembrane protein, it has been proposed that APP might be a receptor, but so far, no ligand has been reported. In the present study, 9 proteins binding to the extracellular domain of APP were identified using a yeast two-hybrid system. After confirming the interactions in the mammalian system, mutated PLP1,members of the FLRT protein family, and KCTD16 were shown to interact with APP. These proteins have been reported to be involved in Pelizaeus-Merzbacher disease（PMD） and axon guidance. Therefore, our results shed light on the mechanisms of physiological function of APP in AD, PMD, and axon guidance.

MRI tracking of human Wharton’s jelly stem cells seeded onto acellular dermal matrix labeled with superparamagnetic iron oxide nanoparticles in burn wounds

Background:In vivo cell tracking after transplantation in regenerative medicine remains an unmet challenge and limits current understanding of the wound healing mechanism through cell-based therapies.This study investigated tracking of human Wharton’s jelly stem cells(hWJSCs)seeded onto an acellular dermal matrix(ADM)and labeled with superparamagnetic iron oxide nanoparti-cles(SPIONs)by magnetic resonance imaging(MRI)in burn injury.Method:The hWJSCs were characterized and assessed for growth kinetics.A total of 30 rats were enrolled in three equal groups.Group 1 underwent scald burn injury left without treatment,the group 2 was treated by an ADM that was prepared from cosmetic surgery skin samples and the group 3 received hWJSCs labeled with SPIONs seeded onto an ADM.Tensile strength was evaluated before and after interventions,real time PCR assessed apoptosis,and Prussian blue staining,scanning electron microscopy(SEM)and MRI were used for the tracking of labeled cells.Results:The hWJSCs exhibited mesenchymal stem cell properties.Population doubling time was 40.1 hours.SPIONs did not show any toxic effect.The hWJSCs seeded onto an ADM decreased Bax and increased Bcl-2 gene expression.Internalization of SPIONs within hWJSCs was confirmed by Prussian blue staining,SEM and MRI until day 21.There was a significant difference between the Young’s moduli of normal skin and the group receiving hWJSCs seeded onto an ADM.Histological observations and SEM imaging confirmed that MRI is an accurate method to track SPION-labeled hWJSCs in vivo.Conclusions:This study showed that SPION labeling coupled with MRI can be used to further understand the fate of stem cells after transplantation in a burn model.

In vitro cytotoxic studies of red algae Portieria hornemannii and Spyridia fusiformis against Dalton’s lymphoma ascite and Ehrlich ascite carcinoma cell lines

Objective:To study the in vitro cytotoxic activities of methanol extract of Portieria hornemannii(P.hornemannii)and Spyridia fusiformis(S.fusiformis)using Dalton’s lymphoma ascite and Ehrlich ascite carcinoma cell lines.Methods:The effect of cytotoxicity of P.hornemannii and S.fusiformis was evaluated with the concentrations(100 to 200μg/mL)and assessed for the antitumour activity vs.the selected cell lines using Trypan blue assay.Results:The methanol extracts of P.hornemannii and S.fusiformis showed potent cytotoxic activity with IC_(50)values of(209.00±0.05)μg/mL and(190.00±0.05)μg/mL against the Dalton’s lymphoma ascite cell line and IC_(50)values of(190.00±0.05)μg/mL and(182.00±0.05)μg/mL against the Ehrlich ascite carcinoma cell line respectively.In vitro cytotoxicity against the tested cancer cell lines showed strong activity by the abnormal activities of algal residue in the normal cells.Conclusions:The methanol solvent residue of red algae(P.hornemannii and S.fusiformis)could be a good candidate.It would be a novel marine resource as a antitumor medicine demonstrated by cytotoxic studies that the above marine algae can be a potential candidate sources as antitumor drugs.