Stem Cell-based Transplantation Therapies Research Articles

Transplantation of Neural Progenitor Cells Derived from Stem Cells from Apical Papilla Through Small-Molecule Induction in a Rat Model of Sciatic Nerve Injury

Background:Stem cell-based transplantation therapy holds promise for peripheral nerve injury treatment, but adult availability is limited. A cell culture protocol utilizing a small-molecule cocktail effectively reprogrammed stem cells from apical papilla (SCAPs) into neural progenitor cells, subsequently differentiating into neuron-like cells. This study aims to evaluate neural-induced SCAPs, with and without small-molecule cocktail, for sciatic nerve repair potential.Methods:A scaffold-free cell sheet technique was used to construct a three-dimensional cell sheet. Subsequently, this cell sheet was carefully rolled into a tube and seamlessly inserted into a collagen conduit, which was then transplanted into a 5 mm sciatic nerve injury rat model. Functional sciatic nerve regeneration was evaluated via toe spread test, walking track analysis and gastrocnemius muscle weight. Additionally, degree of sciatic nerve regeneration was determined based on total amount of myelinated fibers.Results:Small-molecule cocktail induced SCAPs enhanced motor function recovery, evident in improved sciatic function index and gastrocnemius muscle retention. We also observed better host myelinated fiber retention than undifferentiated SCAPs or neural-induced SCAPs without small-molecule cocktail. However, clusters of neuron-like cell bodies (surrounded by sparse myelinated fibers) were found in all cell sheet-implanted groups in the implantation region. This suggests that while the implanted cells likely survived transplantation, integration was poor and would likely hinder long-term recovery by occupying the space needed for host nerve fibers to project through.Conclusion:Neural-induced SCAPs with small-molecule cocktail demonstrated promising benefits for nerve repair; further research is needed to improve its integration and optimize its potential for long-term recovery.

Stem Cell Transplantation Therapy and Neurological Disorders: Current Status and Future Perspectives.

Simple SummaryThis review highlights the scope of available treatment options for neurological diseases, especially stem cell transplantation therapy, which provides new hope. The health sector continues to grow effectively, developing new ideas for saving lives and making complex processes more accessible, such as stem cell transplantation therapy. The treatment of individual neurological disorders is associated with different pathophysiological conditions, so transplantation therapy must be performed under optimal conditions with minimal risk. The promise of stem cell transplantation increases every day, with excellent animal models and small-scale observations in human trials. Stem cell therapy provides satisfactory data that support rational therapeutic purposes.Neurodegenerative diseases are a global health issue with inadequate therapeutic options and an inability to restore the damaged nervous system. With advances in technology, health scientists continue to identify new approaches to the treatment of neurodegenerative diseases. Lost or injured neurons and glial cells can lead to the development of several neurological diseases, including Parkinson’s disease, stroke, and multiple sclerosis. In recent years, neurons and glial cells have successfully been generated from stem cells in the laboratory utilizing cell culture technologies, fueling efforts to develop stem cell-based transplantation therapies for human patients. When a stem cell divides, each new cell has the potential to either remain a stem cell or differentiate into a germ cell with specialized characteristics, such as muscle cells, red blood cells, or brain cells. Although several obstacles remain before stem cells can be used for clinical applications, including some potential disadvantages that must be overcome, this cellular development represents a potential pathway through which patients may eventually achieve the ability to live more normal lives. In this review, we summarize the stem cell-based therapies that have been explored for various neurological disorders, discuss the potential advantages and drawbacks of these therapies, and examine future directions for this field.

Synthesis and secretome release by human bone marrow mesenchymal stem cell spheroids within three-dimensional collagen hydrogels: Integrating experiments and modelling.

Myocardial infarction results in loss of cardiac cell types, inflammation, extracellular matrix (ECM) degradation, and fibrotic scar. Transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) is being explored as they could differentiate into cardiomyocyte-like cells, integrate into host tissue, and enhance resident cell activity. The ability of these cells to restore lost ECM, remodel the inflammatory scar tissue, and repair the injured myocardium remains unexplored. We here elucidated the synthesis and deposition of ECM (e.g., elastin, sulfated glycosaminoglycans, hyaluronan, collagen type III, laminin, fibrillin, lysyl oxidase, and nitric oxide synthases), matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), and other secretome (cytokines, chemokines, and growth factors) in adult human BM-MSC spheroid cultures within three-dimensional collagen gels. The roles of species-specific type I collagen and 5-azacytadine were assessed over a 28-day period. Results revealed that human collagen (but not rat-derived) suppressed MSC proliferation and survival, and MSCs synthesized and released a variety of ECM proteins and secretome over the 28 days. Matrix deposition is at least an order of magnitude lower than their release levels at every time point, most possibly due to elevated MMP levels and interleukins with a concomitant decrease in TIMPs. Matrix synthesis over the 28-day period was fitted to a competitive inhibition form of Michaelis-Menten kinetics, and the production and decay rates of ECM, MMPs, and TIMPs, along with the kinetic model parameters quantified. Such an integrated experimental and modelling approach would help elucidate the critical roles of various parameters (e.g., cell encapsulation and delivery vehicles) in stem cell-based transplantation therapies.

Effect of biphasic electrical stimulation on the proliferation and differentiation of olfactory bulb neural precursor cells

Objective To explore the effect of biphasic electrical stimulation (BES) on the proliferation and differentiation of rats olfactory bulb neural precursor cells (OB NPCs). Methods OB NPCs of one day old neonatal rats were isolated, cultured, passaged and identified. They were randomly divided into a control group and an electrical stimulation (ES) group. The OB NPCs in the ES group were exposed to BES with a 50 mV/mm or 100 mV/mm electric field for 24 hours with a pulse width of 8 ms, while the control group was not given electrical stimulation. The immunofluorescent technique and 3(4, 5 dimethythiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT) colorimetric assay were used to assess the cells′ proliferation and differentiation. Results The cell viability and the number of glial fibrillary acidic protein positive cellsin the ES group were significantly higher than in the control group. Conclusions BES may be used as an auxiliary technique for improving cell survival and differentiation in stem cell-based transplantation therapy as it can promote proliferation and differentiation, at least of OB NPCs. Key words: Electrical stimulation; Olfactory bulb; Neural stem cells; Proliferation; Differentiation; Neural repair; Neural regeneration; Nerve injury

Treating Parkinson's disease in the 21st century: Can stem cell transplantation compete?

The characteristic and selective degeneration of a unique population of cells—the nigrostriatal dopamine (DA) neurons—that occurs in Parkinson’s disease (PD) has made the condition an iconic target for cell replacement therapies. Indeed, transplantation of fetal ventral mesencephalic cells into the DA-deficient striatum was first trialled nearly 30 years ago, at a time when other treatments for the disease were less well developed. Over recent decades standard treatments for PD have advanced, and newer biological therapies are now emerging. In the 21st century, stem cell technology will have to compete alongside other sophisticated treatments, including deep brain stimulation and gene therapies. In this review we examine how stem cell–based transplantation therapies compare with these novel and emerging treatments in the management of this common condition. J. Comp. Neurol. 522:2802–2816, 2014.

Potential protective effect of biphasic electrical stimulation against growth factor-deprived apoptosis on olfactory bulb neural progenitor cells through the brain-derived neurotrophic factor–phosphatidylinositol 3′-kinase/Akt pathway

Stem cell therapy may provide a therapeutic method for the replacement and regeneration of damaged neurons of the central nervous system. However, neural stem cells (NSCs) and neural precursor cells (NPCs) are especially vulnerable after transplantation due to a lack of sufficient growth factors at the transplant site. Electrical stimulation (ES) has recently been found to participate in the regulation of cell proliferation, growth, differentiation, and migration, but its underlying anti-apoptotic effects remain unclear. This study investigated the protective effects of biphasic electrical stimulation (BES) on olfactory bulb NPCs against growth factor-deprived apoptosis, examining the survival and apoptotic features of the cells. Differentiation was assessed by neuronal and glial markers. Brain-derived neurotrophic factor-phosphatidylinositol 3'-kinase (BDNF)-PI3K/Akt pathway activation was determined by enzyme-linked immunosorbent assay and Western blot. The chemical inhibitor wortmannin was used to inhibit the PI3K/Akt pathway. BES exerts a protective effect against growth factor-deprived apoptosis in the NPCs. BES enhanced cell survival and decreased the apoptotic/necrotic rate. Expression of phosphorylated Akt and BDNF secretion increased with BES for 12 h. Furthermore, the protective effects of BES were inhibited by blocking PI3K/AKT signalling. These results suggest that BES prevents growth factor-deprived apoptosis through the BDNF-PI3K/Akt signalling. This work strengthens the opinion that BES may be used as an auxiliary strategy for improving cell survival and preventing cell apoptosis in stem cell-based transplantation therapy.

Human nerual stem cells for brain repair.

Cell replacement therapy and gene transfer to the diseased or injured brain have provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases including Parkinson disease, Huntington disease, amyotrophic lateral sclerosis (ALS), Alzheimer disease, multiple sclerosis (MS), stroke, spinal cord injury and brain cancer. In recent years, neurons and glial cells have successfully been generated from neural stem cells, and extensive efforts by investigators to develop neural stem cell-based transplantation therapies have been carried out. We review here notable experimental and pre-clinical studies we have previously conducted involving human neural stem cell-based cell- and gene-therapies for Parkinson disease, Huntington disease, ALS, stroke and brain cancer.

Emerging cues mediating astroglia lineage restriction of progenitor cells in the injured/diseased adult CNS

Other than specific neurogenic regions, the adult central nervous system (CNS) is not conducive for neuronal regeneration and neurogenesis, particularly at sites of injury or neurodegeneration. Engraftment of neural stem/progenitor cells into non-neurogenic regions or sites of injury/disease invariably results mainly in astroglia differentiation. The reasons for such a lineage restriction have not been well defined. Recent findings have brought to light some underlying novel mechanistic basis for this preferential differentiation into astroglia. The more oxidized state of pathological brain tissue leads to upregulation of the protein deacetylase sirtuin 1 (Sirt1). Sirt1 appears to stabilize a co-repressor complex of Hairy/enhancer of split ( Hes)1, thereby suppressing expression of the proneuronal transcription factor Mash1, and directs progenitor cell differentiation towards the glia lineage. Sirt1 upregulated by CNS inflammation may also inhibit neuronal differentiation. Myelin-associated inhibitors such as Nogo, acting through the Nogo-66 receptor (NgR), also appear to promote neural stem/progenitor cell differentiation into astrocytes. Understanding the molecular basis of glia lineage restriction of neural progenitors in the injured or diseased CNS would provide handles to improving the success of stem cell-based transplantation therapy.

Functional polymer hydrogels for embryonic stem cell support

Embryonic stem (ES) cells are pluripotent cells with the ability to differentiate among all embryonic and adult cell lineages. Derivation of human ES cells opened up the way for treatment of many serious disorders by stem cell-based transplantation therapy. One of the most exciting challenges in development of transplantation therapies is to repair the damaged part of the organ or tissue by transplantation of undifferentiated ES cells or their differentiated derivatives within three-dimensional polymer scaffold. This method allows both renewal of structure and restoration of function of the organ. To address this issue, new polymer hydrogels were synthesized and tested. Cationic hydrogel slabs were synthesized by bulk radical copolymerization of 2-hydroxyethyl methacrylate (HEMA) and 2-(dimethylamino)ethyl methacrylate (DMAEMA) with ethylene dimethacrylate (EDMA) or 1-vinyl-2-pyrrolidone (VP) with N,N'-divinylethyleneurea (DVEU) or EDMA in the presence of saccharose or NaCl as a porogen. Swelling studies of the synthesized copolymers showed a high water content in the swollen state. Biocompatibility was studied with the use of feeder-independent mouse ES cell line D3. Cells grown either on the surface or inside synthesized polymer slabs suggest that the tested slabs are not toxic. The ability of ES cells to proliferate was only partially limited in PHEMA slabs crosslinked with EDMA compared with standard culture conditions. When cultured for a limited period of time, ES cells retained their undifferentiated state independently of properties of the hydrogel slabs, presence or absence of surface charges, type of crosslinking agent and matrix (PHEMA or PVP). Notably, prolonged culture in superporous hydrogel slabs initiated ES cell differentiation. Compared with unmodified PHEMA, the number of proliferating ES cells was still lower in the presence of cationic polymers.

Human embryonic stem cells: research, ethics and policy.

The use of human embryos for research on embryonic stem (ES) cells is currently high on the ethical and political agenda in many countries. Despite the potential benefit of using human ES cells in the treatment of disease, their use remains controversial because of their derivation from early embryos. Here, we address some of the ethical issues surrounding the use of human embryos and human ES cells in the context of state-of-the-art research on the development of stem cell based transplantation therapy.