Stem cell-based therapy for Parkinson’s disease with a focus on human endometrium-derived mesenchymal stem cells

Parkinson’s disease (PD) as an increasing clinical syndrome is a multifunctional impairment with systemic involvement. At present, therapeutic approaches such as l -3,4-dihydroxy-phenylalanine replacement therapy, dopaminergic agonist administration, and neurosurgical treatment intend to relieve PD symptoms which are palliative and incompetent in counteracting PD progression. These mentioned therapies have not been able to replace the lost cells and they could not effectively slow down the relentless neurodegenerative process. Till now, there is a lack of eligible treatment for PD, and stem cells therapy recently has been considered for PD treatment. In this review, we demonstrate how human stem cell technology especially human endometrium-derived stem cells have made advancement as a therapeutic source for PD compared with other treatments.     

Dental mesenchymal stromal/stem cells in different microenvironments— implications in regenerative therapy

Current research data reveal microenvironment as a significant modifier of physical functions, pathologic changes, as well as the therapeutic effects of stem cells. When comparing regeneration potential of various stem cell types used for cytotherapy and tissue engineering, mesenchymal stem cells (MSCs) are currently the most attractive cell source for bone and tooth regeneration due to their differentiation and immunomodulatory potential and lack of ethical issues associated with their use. The microenvironment of donors and recipients selected in cytotherapy plays a crucial role in regenerative potential of transplanted MSCs, indicating interactions of cells with their microenvironment indispensable in MSC-mediated bone and dental regeneration. Since a variety of MSC populations have been procured from different parts of the tooth and tooth-supporting tissues, MSCs of dental origin and their achievements in capacity to reconstitute various dental tissues have gained attention of many research groups over the years. This review discusses recent advances in comparative analyses of dental MSC regeneration potential with regards to their tissue origin and specific microenvironmental conditions, giving additional insight into the current clinical application of these cells.     

From stem cells to red blood cells:how far away from the clinical application?

The generation of red blood cells(RBCs)from stem cells provides a solution for deficiencies in blood transfusion.Currently,primary hematopoietic stem cells,embryonic stem cells and induced pluripotent stem cells have shown the potential to produce fully mature RBCs.Here,we discuss the advantages,induction protocols,progress and possible clinical applications of stem cells in RBC production.     

Lysis of autologous tumor cells by blood lymphocytes activated in autologous mixed lymphocyte tumor cell culture — No correlation with the postsurgical clinical course

Summary Mixed lymphocyte tumor cell cultures (MLTC) were initiated with cells collected at the time of surgery from 62 patients with the following diagnoses: 12 squamous cell carcinoma, 14 adenocarcinoma of the lung, 17 osteosarcomas, and 16 soft tissue sarcomas. The lytic effect generated against autologous tumor cells was tested on the 7th day. These patients had been part of previous evaluation, which revealed that the lysis of autologous tumor cells by freshly collected lymphocytes correlated with the postsurgical clinical course. Patients with long survival exhibited autotumor lysis without previous activation. Blood lymphocytes of about half of the primarily nonreactive patients were stimulated for lytic function in MLTC. However, this parameter showed no correlation with the clinical course.     

TGFβ2-induced tenogenesis impacts cadherin and connexin cell-cell junction proteins in mesenchymal stem cells

Tenogenic differentiation of stem cells is needed for tendon tissue engineering approaches. A current challenge is the limited information on the cellular-level changes during tenogenic induction. Tendon cells in embryonic and adult tendons possess an array of cell-cell junction proteins that include cadherins and connexins, but how these proteins are impacted by tenogenic differentiation is unknown. Our objective was to explore how tenogenic induction of mesenchymal stem cells (MSCs) using the transforming growth factor (TGF)β2 impacted protein markers of tendon differentiation and protein levels of N-cadherin, cadherin-11 and connexin-43. MSCs were treated with TGFβ2 for 21 days. At 3 days, TGFβ2-treated MSCs developed a fibroblastic morphology and significantly decreased levels of N-cadherin protein, which were maintained through 21 days. Similar decreases in protein levels were found for cadherin-11. Connexin-43 protein levels significantly increased at 3 days, but then decreased below control levels, though not significantly. Protein levels of scleraxis and tenomodulin were significantly increased at day 14 and 21, respectively. Taken together, our results indicate that TGFβ2 is an inducer of tendon marker proteins (scleraxis and tenomodulin) in MSCs and that tenogenesis alters the protein levels of N-cadherin, cadherin-11 and connexin-43. These findings suggest a role for connexin-43 early in tenogenesis, and show that early-onset and sustained decreases in N-cadherin and cadherin-11 may be novel markers of tenogenesis in MSCs.     

Isolation and characterization of mesenchymal stem cells derived from bone marrow of patients with Parkinson’s disease

Mesenchymal stem cells (MSCs) are capable of self-renewing and differentiating into multiple tissues; they are expected to become a source of cells for regenerative therapy. Compared to allogeneic MSCs, autologous MSCs from patients needing cell-based therapy may be an ideal alternative stem cell source. However, characterizations of MSCs from a disease state remains extremely limited. Therefore, we have isolated and characterized MSCs from Parkinson's disease (PD) patients and compared them with MSCs derived from normal adult bone marrow. Our results show that PD-derived MSCs are similar to normal MSCs in phenotype, morphology, and multidifferentiation capacity. Moreover, PD-derived MSCs are capable of differentiating into neurons in a specific medium with up to 30% having the characteristics of dopamine cells. At last, PD-derived MSCs could inhibit T-lymphocyte proliferation induced by mitogens. These findings indicate that MSCs derived from PD patients' bone marrow may be a promising cell type for cellular therapy and somatic gene therapy applications.     

Phase Ⅰ/Ⅱ randomized controlled trial of autologous bone marrow-derived mesenchymal stem cell therapy for chronic stroke

AIM To examine the safety and efficacy of mesenchymal stem cell(MSC) therapy for intracerebral haemorrhage with neurological dysfunctions for a year.METHODS MSC were ex vivo expanded from 29 mL(17-42 mL) autologous bone marrow. Patients were randomized to have two intravenous injections of autologous MSC or placebos in four weeks apart. Neurological functions and clinical outcomes were monitored before treatment and at 12~(th), 16~(th), 24~(th), 36~(th) and 60~(th) week upon completion of~(th)e treatment. RESULTS A mean of 4.57 × 10~7(range: 1.43 × 10~7-8.40 × 10~7) MSC per infusion was administered accounting to 8.54 × 10~5(2.65 × 10~5-1.45 × 10~6) per kilogram body weight in two occasions. There was neither adverse event at time of administration nor sign of de novo tumour development among patients after monitoring for a year post MSC therapy. Neuro-restoration and clinical improvement in terms of modified Barthel index, functional independence measure and extended Glasgow Outcome Scale were evident among patients having MSC therapy compared to patients receiving placebos. CONCLUSION Intravenous administration of autologous bone marrowderived MSC is safe and has the potential of improving neurological functions in chronic stroke patients with severe disability.     

WJSC 6th Anniversary Special Issues（2）:Mesenchymal stem cells Enhancing the efficacy of mesenchymal stem cell therapy

Mesenchymal stem cell(MSC)therapy is entering a challenging phase after completion of many preclinical and clinical trials.Among the major hurdles encountered in MSC therapy are inconsistent stem cell potency,poor cell engraftment and survival,and age/disease-related host tissue impairment.The recognition that MSCs primarily mediate therapeutic benefits through paracrine mechanisms independent of cell differentiation provides a promising framework for enhancing stem cell potency and therapeutic benefits.Several MSC priming approaches are highlighted,which will likely allow us to harness the full potential of adult stem cells for their future routine clinical use.     

Cell therapy for macular degeneration—first phase Ⅰ/Ⅱ pluripotent stem cell-based clinical trial shows promise

<正>Embryonic stem(ES)cells,a type of pluripotent stem cells(PSCs)that are derived from the inner cell mass of blastocysts,have been discovered for more than three decades[1].Given the almost infinite self-renewal capacity and the potential to differentiate into any specific cell type in an individual,ES cells and PSCs have brought hope for the treatment of many unmet diseases.However,the advantages of PSCs—the highly proliferative and plastic capacities,also give rise to concerns regarding the development of tumors     

Are mesenchymal stem cells in rheumatoid arthritis the good or bad guys?

The advancements in our understanding of the inflammatory and immune mechanisms in rheumatoid arthritis (RA) have fuelled the development of targeted therapies that block cytokine networks and pathogenic immune cells, leading to a considerable improvement in the management of RA patients. Nonetheless, no therapy is curative and clinical remission does not necessarily correspond to non-progression of joint damage. Hence, the biomedical community has redirected scientific efforts and resources towards the investigation of other biological aspects of the disease, including the mechanisms driving tissue remodelling and repair. In this regard, stem cell research has attracted extraordinary attention, with the ultimate goal to develop interventions for the biological repair of damaged tissues in joint disorders, including RA. The recent evidence that mesenchymal stem cells (MSCs) with the ability to differentiate into cartilage are present in joint tissues raises an opportunity for therapeutic interventions via targeting intrinsic repair mechanisms. Under physiological conditions, MSCs in the joint are believed to contribute to the maintenance and repair of joint tissues. In RA, however, the repair function of MSCs appears to be repressed by the inflammatory milieu. In addition to being passive targets, MSCs could interact with the immune system and play an active role in the perpetuation of arthritis and progression of joint damage. Like MSCs, fibroblast-like synoviocytes (FLSs) are part of the stroma of the synovial membrane. During RA, FLSs undergo proliferation and contribute to the formation of the deleterious pannus, which mediates damage to articular cartilage and bone. Both FLSs and MSCs are contained within the mononuclear cell fraction in vitro, from which they can be culture expanded as plastic-adherent fibroblast-like cells. An important question to address relates to the relationship between MSCs and FLSs. MSCs and FLSs could be the same cell type with functional specialisation or represent different functional stages of the same stromal lineage. This review will discuss the roles of MSCs in RA and will address current knowledge of the relative identity between MSCs and FLSs. It will also examine the immunomodulatory properties of the MSCs and the potential to harness such properties for the treatment of RA.     

WJSC 6th Anniversary Special Issues（2）:Mesenchymal stem cells Brain mesenchymal stem cells:The other stem cells of the brain?

Multipotent mesenchymal stromal cells(MSC),have the potential to differentiate into cells of the mesenchymal lineage and have non-progenitor functions including immunomodulation.The demonstration that MSCs are perivascular cells found in almost all adult tissues raises fascinating perspectives on their role in tissue maintenance and repair.However,some controversies about the physiological role of the perivascular MSCs residing outside the bone marrow and on their therapeutic potential in regenerative medicine exist.In brain,perivascular MSCs like pericytes and adventitial cells,could constitute another stem cell population distinct to the neural stem cell pool.The demonstration of the neuronal potential of MSCs requires stringent criteria including morphological changes,the demonstration of neural biomarkers expression,electrophysiological recordings,and the absence of cell fusion.The recent finding that brain cancer stem cells can transdifferentiate into pericytes is another facet of the plasticity of these cells.It suggests that the perversion of the stem cell potential of pericytes might play an even unsuspected role in cancer formation and tumor progression.     

Neuroprotective effects of human mesenchymal stem cells on neural cultures exposed to 6-hydroxydopamine: implications for reparative therapy in Parkinson’s disease

Stem cell (SC) transplantation represents a promising tool to treat neurodegenerative disorders, such as Parkinson's disease (PD), but positive therapeutic outcomes require elucidation of the biological mechanisms involved. Therefore, we investigated human Mesenchymal SCs (hMSCs) ability to protect murine differentiated Neural SCs (mdNSCs) against the cytotoxic effects of 6-hydroxydopamine (6-OHDA) in a co-culture model mimicking the in vivo neurovascular niche. The internalization of 6-OHDA mainly relies on its uptake by the dopamine active transporter (DAT), but its toxicity could also involve other pathways. We demonstrated that mdNSCs consistently expressed DAT along the differentiative process. Exposure to 6-OHDA did not affect hMSCs, but induced DAT-independent apoptosis in mdNSCs with generation of reactive oxygen species and caspases 3/7 activation. The potential neuroprotective action of hMSCs on mdNSCs exposed to 6-OHDA was tested in different co-culture conditions, in which hMSCs were added to mdNSCs prior to, simultaneously, or after 6-OHDA treatment. In the presence of the neurotoxin, the majority of mdNSCs acquired an apoptotic phenotype, while co-cultures with hMSCs significantly increased their survival (up to 70%) in all conditions. Multiplex human angiogenic array analysis on the conditioned media demonstrated that cytokine release by hMSCs was finely modulated. Moreover, sole growth factor addition yielded a similar neuroprotective effect on mdNSCs. In conclusion, our findings demonstrate that hMSCs protect mdNSCs against 6-OHDA neurotoxicity, and rescue cells from ongoing neurodegeneration likely through the release of multiple cytokines. Our findings provide novel insights for the development of therapeutic strategies designed to counteract the neurodegenerative processes of PD.     

Human peripheral blood-derived mesenchymal stem cells with NTRK1 over-expression enhance repairing capability in a rat model of Parkinson’s disease

The potency of mesenchymal stem cells (MSCs) for tissue repair and regeneration is mainly based on their ability to secret beneficial molecules. Administration of MSCs has been proposed as an innovative approach and is proved by a number of clinical trials to a certain degree for the therapy of many diseases including Parkinson’s disease (PD). However, the efficacy of MSCs alone is not significant. We investigated the effect of neurotrophic tyrosine receptor kinase 1 (NTRK1) overexpressed peripheral blood MSCs (PB-MSCs) on PD rat model. NTRK1 was overexpressed in PB-MSCs, which were then injected into PD rat model, Dopaminergic (DA) neuron regeneration and rotational performance was assessed. We found that DA neuron repair was increased in lesion site, rotational performance was also improved in MSC transplanted PD rat, with most potent effect in NTRK1 overexpressed PB-MSC transplanted PD rat. Our results indicate that overexpression of NTRK1 in MSCs could be an optimized therapeutic way via MSCs for PD treatment.     

Doxorubicin-induced senescence through NF-κB affected by the age of mouse mesenchymal stem cells

The senescence is proposed as a defense mechanism against many anticancer drugs. This complication is marked by differences in cell appearance and inner structures underlying the impairment in function. In this experiment, doxorubicin-induced senescence was assessed in mesenchymal stem cells (MSCs) isolated from the bone marrow of different-aged Balb/c mice (1, 8, and 16 months old). In addition, doxorubicin kinetics in culture medium were investigated to compare the drug absorption rate by different-aged MSCs. Several methods were exerted including Sandwich ELISA for NF-κB activation, propidium iodide staining for cell cycle analysis, Flow-fluorescent in-situ hybridization (Flow-FISH) assay for telomere length measurement, and specific staining for evaluation of β-galactosidase. Determination of doxorubicin in a medium was performed by high-performance liquid chromatography technique. Following doxorubicin exposure, cells underwent substantial telomere shortening, cell cycle arresting in G2 phase, and increased β-galactosidase activity. Interestingly, the enhanced level of NF-κB was observed in all age groups. The highest and lowest sensitivity to telomere shortening attributed to 1- and 8-month-old MSCs, respectively. In consistent with Flow-FISH results, the β-galactosidase activity was higher in young-aged MSCs after treatment. Statistical analysis indicated a correlation between the reduction of telomere length and cessation in G2 phase. Regarding the obtained kinetics equations, the rate of doxorubicin absorption by all aged MSCs followed the same trend. In conclusion, the changing of some elements involved in doxorubicin-induced senescence can be affected by the age of the cells significantly in young MSCs than two other age groups. Hereupon, these changing patterns can open new insights to develop anticancer therapeutic strategies.     

Repairing cartilage defects with bone marrow mesenchymal stem cells induced by CDMP and TGF-β1

The aim of this study was to explore the ability for chondrogenic differentiation of bone marrow mesenchymal stems cells (BMSCs) induced by either cartilage-derived morphogenetic protein 1 (CDMP-1) alone or in the presence of transforming growth factor-β₁ (TGF-β₁) in vivo and in vitro. BMSCs and poly-lactic acid/glycolic acid copolymer (PLGA) scaffold were analyzed for chondrogenic capacity induced by CDMP-1 and TGF-β₁ in vivo and in vitro. Chondrogenic differentiation of BMSCs into chondrocytes using a high density pellet culture system was tested, whether they could be maintained in 3-D PLGA scaffold instead of pellet culture remains to be explored. Under the culture of high-density cell suspension and PLGA frame, BMSCs were observed the ability to repair cartilage defects by either CDMP-1 alone or in the presence of TGF-β₁ in vitro. Then the cell-scaffold complex was implanted into animals for 4 and 8 weeks for in vivo test. The content of collagen type II and proteoglycan appeared to increase over time in the constructs of the induced groups (CDMP in the presence of TGF-β₁), CDMP group and TGF group. However, the construct of the control group did not express them during the whole culture time. At 4 and 8 weeks, the collagen type II expression of the induced group was higher than the sum of TGF group and CDMP group by SSPS17.0 analysis. BMSCs and PLGA complex induced by CDMP-1 and TGF- β₁ can repair cartilage defects more effectively than that induced by CDMP-1 or TGF-β₁ only.     

How to influence the mesenchymal stem cells fate? Emerging role of ectoenzymes metabolizing nucleotides

Extracellular purines, principally adenosine triphosphate and adenosine, are among the oldest evolutionary and widespread chemical messengers. The integrative view of purinergic signaling as a multistage coordinated cascade involves the participation of nucleotides/nucleosides, their receptors, enzymes metabolizing extracellular nucleosides and nucleotides as well as several membrane transporters taking part in the release and/or uptake of these molecules. In view of the emerging data, it is evident and widely accepted that an extensive network of diverse enzymatic activities exists in the extracellular space. The enzymes regulate the availability of nucleotide and adenosine receptor agonists, and consequently, the course of signaling events. The current data indicate that mesenchymal stem cells (MSCs) and cells induced to differentiate exhibit different sensitivity to purinergic ligands as well as a distinct activity and expression profiles of ectonucleotidases than mature cells. In the proposed review, we postulate for a critical role of these enzymatic players which, by orchestrating a fine-tune regulation of nucleotides concentrations, are integrally involved in modulation and diversification of purinergic signals. This specific hallmark of the MSC purinome should be linked with cell-specific biological potential and capacity for tissue regeneration. We anticipate this publication to be a starting point for scientific discussion and novel approach to the in vitro and in vivo regulation of the MSC properties.     

WJSC 6th Anniversary Special Issues（2）:Mesenchymal stem cells Umbilical cord-derived mesenchymal stem cells:Their advantages and potential clinical utility

Human umbilical cord(UC)is a promising source of mesenchymal stem cells(MSCs).Apart from their prominent advantages,such as a painless collection procedure and faster self-renewal,UC-MSCs have shown the ability to differentiate into three germ layers,to accumulate in damaged tissue or inflamed regions,to promote tissue repair,and to modulate immune response.There are diverse protocols and culture methods for the isolation of MSCs from the various compartments of UC,such as Wharton’s jelly,vein,arteries,UC lining and subamnion and perivascular regions.In this review,we give a brief introduction to various compartments of UC as a source of MSCs and emphasize the potential clinical utility of UC-MSCs for regenerative medicine and immunotherapy.     

Testing alternatives: the use of adipose-derived mesenchymal stem cells to slow neurodegeneration in a rat model of Parkinson’s disease

Molecular Biology Reports - Parkinson’s disease (PD) is a chronic neurodegenerative disease. Unfortunately, the effectiveness of anti-Parkinson treatments gradually diminishes owing to the...