Current Stem Cell Research & Therapy - Volume 10, Issue 2, 2015

Osteoarthritis (OA) is the most common degenerative joint disorder worldwide. OA represents an increasing threat to the quality of life of affected persons as well as for health resources expenditure. The incapability of cartilage to heal has been long time regarded as the major cause of progressive joint degeneration and functional impairment. Recent reports about the presence of progenitor cell populations within adult normal and OA cartilage invite to a reconsideration of the mechanisms involved in the onset and propagation of the disease as well as of the causes that are preventing the endogenous progenitors to recompose a functional extracellular matrix. The interplay between chronic joint inflammation, tissue functional and pathological load and the mechanosensitivity of progenitor cell populations are not yet fully understood. Elucidation of these complex correlations at molecular level could lead to identification of biomarkers for early detection, finding targets for the causal treatment of OA. The use of local progenitor populations in various cartilage regeneration strategies proves to be a fruitful avenue for research and clinical applications.

Consisting of seed cells and scaffold, regenerative medicine provides a new way for the repair and regeneration of tissue and organ. Collagen/hydroxyapatite (HA) biocomposite scaffold is highlighted due to its advantageous features of two major components of bone matrix: collagen and HA. The aim of this study is to investigate the effect of internal structure of collagen/HA scaffold on the fate of rat mesenchymal stem cells (MSCs). The internal structure of collagen/HA scaffold was characterized by micro-CT. It is found that the porosity decreased while average compressive modulus increased with the increase of collagen proportion. Within the collagen proportion of 0.35%, 0.5% and 0.7%, the porosities were 89.08%, 78.37% and 75.36%, the pore sizes were 140.6±75.5 μm, 133.9±48.4 μm and 160.7±119.6 μm, and the average compressive moduli were 6.74±1.16 kPa, 8.82±2.12 kPa and 23.61±8.06 kPa, respectively. Among these three kinds of scaffolds, MSCs on the Col 0.35/HA 22 scaffold have the highest viability and the best cell proliferation. On the contrary, the Col 0.7/HA 22 scaffold has the best ability to stimulate MSCs to differentiate into osteoblasts in a relatively short period of time. In vivo research also demonstrated that the internal structure of collagen/HA scaffold has significant effect on the cell infiltration. Therefore, precise control of the internal structure of collagen/HA scaffold can provide a more efficient carrier to the repair of bone defects.

Bone marrow-derived mesenchymal stem cells hold great potential for cytotherapeutics of neurodegenerative disorders, including Parkinson’s disease. The neurotrophic factor neurturin can rescue dopaminergic neurons damaged during the disease process. Lmx1α can promote mesencephalic dopaminergic differentiation during embryogenesis. In this study, we tested a cytotherapeutic strategy combining NTN/Lmx1α gene therapy and cell transplantation to ameliorate disease progression in hemiparkinsonian rhesus. Rhesus BMSCs were prepared for autologous grafting by transfection with recombinant adenoviral vectors expressing secreted NTN and Lmx1α,and cultured in the presence of induce factors, particularly the Lmx1α regulatory factor sonic hedgehog, to guide dopaminergic differentiation. These induced rh-BMSCs exhibited gene/protein expression phenotypes resembling nigral dopaminergic neurons. They survived and retained dopaminergic function following stereotaxic injection into the MPTPlesioned right-side substantia nigra as indicated by SPECT measurement of DAT activity. Injected cells preserved and supplemented the remaining endogenous population of dopamine neurons (TH-positive cell ipsilateral/contralateral ratio was 56.81% ± 7.28% vs. 3.86%±1.22% in vehicle-injected controls; p<0.05). Cell injection also partially restored motor function and reduce apomorphine-evoked rotation (p<0.05). Moreover, function recovery occurred earlier than in previous studies on injected BMSCs. Our findings demonstrate a promising strategy for restoration of PD-associated motor dysfunction by transplantation of autologous BMSCs overexpressing NTN/Lmx1α.

Administration of mesenchymal stem cells (MSCs) that have a reliable potential for chondrogenic differentiation is a promising approach currently employed to treat articular cartilage lesions (focal defects and osteoarthritis) in patients as a mean to enhance the poor intrinsic capabilities of this specialized tissue for self-repair. However, there is still a critical need for improved designs, as reproduction of a native structural and functional unit in sites of cartilage damage is not occurring upon implantation of such cells. With the availability of optimized gene transfer systems, gene therapy offers powerful tools to stimulate the chondrogenic process in MSCs via the effective, safe, and durable delivery of candidate sequences with chondroprotective and/or chondroregenerative properties, both in vitro and in experimental models of cartilage lesions in vivo. In the present article, we provide an overview of the current advances in gene- and stem cell-based treatments employed to promote cartilage repair in focal defects and for osteoarthritis, and discuss the challenges that remain to be addressed for a safe translation of such procedures into the clinics.

Our goal was to address if intermittent hypobaric hypoxia (IHH) exposure can help to increase the number of peripheral blood circulating progenitor cells and side population (SP) stem cells, in order to establish the usefulness of this intervention for skeletal muscle repair, because these cells play a role in tissue regeneration. Male Sprague-Dawley rats were studied in two basal states: untrained and trained and compared with 1, 3, 7 and 14 days stages of damage recovery of trained rats that had suffered skeletal muscle injury. Three experimental groups were studied: rats with passive recovery (CTRL); rats exposed to IHH after muscle damage (HYP); and, trained rats that, in addition to IHH, performed light aerobic exercise sessions (EHYP). We observed an increase in hematopoietic stem cells (HSCs) (mean = 0.153% of cells) and endothelial progenitor cells (EPCs) (mean = 0.0020 % of cells) in EHYP on day 7. Also these cells showed characteristics of more primitive progenitors in comparison to the other experimental groups (mean = 0.107 % of cells), as deduced by retention of the promising fluorescent probe Vybrant Dye Cycle Violet. We concluded that intermittent exposure to hypobaric hypoxia in combination with light aerobic exercise increased the number of HSCs and EPCs on the 7th day in EHYP group, although the exercise-induced stimulus showed a reverse effect on SP kinetics.

Oral squamous cell carcinoma (OSCC) is amongst the most prevalent form of cancer worldwide with its predominance in the Indian subcontinent due to its etiological behavioral pattern of tobacco consumption. Late diagnosis, low therapeutic response and aggressive metastasis are the foremost confounders accountable for the poor 5 year survival rate of OSCC. These failures are attributed to the existence of “Cancer Stem cell (CSC)” subpopulation within the tumour environment. Quiescence, apoptotic evasion, resistance to DNA damage, abnormal expression of drug transporter pumps and in vivo tumorigenesis are the defining hallmarks of CSC phenotype. These CSCs have been distinguished from the tumor mass by determining the expression patterns of cell surface proteins, specific stemness markers and quantifying the cellular activities such as drug efflux & aldehyde dehydrogenase activity. Hence, it is necessary to understand the underlying mechanisms that regulate the CSC features in tumor development, metastasis and response to chemotherapy. Increasing evidence suggests that majority of malignant cells eventually undergoing Epithelial-Mesenchymal transition (EMT) share many biological characteristics with CSCs. Thus, this review encompasses the functional relevance of CSC and EMT markers in OSCC population with a hope to elucidate the fundamental mechanisms underlying cancer progression and to highlight the most relevant epigenetic mechanisms that contribute to the regulation of CSC features. We further aimed to explore the causal effects of nicotine, a major tobacco carcinogen, on epigenetic mechanisms regulating the OSCC CSCs and EMT markers which unravels the undisputable contribution of tobacco in oral carcinogenesis.

Induced pluripotent stem (iPS) cells were created from mouse fibroblasts by induced expression of Yamanaka factors, Oct3/4, Sox2, Klf4, and c-Myc. This technique has quickly resulted in an exponential increase in the amount of pluripotency studies, and has provided a valuable tool in regenerative medicine. At the same time, many methodologies to generate iPS cells have been reported, and are comprised mainly of viral methods and non-viral methods. Although viral methods may not be applicable for clinical applications, various nonviral methods have been reported in recent years, including DNA vector-based approaches, transfection of mRNA, transduction of reprogramming proteins, and use of small molecule compounds. This review summarizes and evaluates these non-viral methods.

Alternative splicing (AS) generates multiple mature mRNAs from a single pre-mRNA, so AS is the main contributor for the diversity of the proteins, participating in most of the cellular processes. For pluripotent stem cells (PSCs), great effort has been made to search for pluripotency-related genes and their regulatory mechanisms. However, the sophisticated regulation still remains to be clear. Recent studies indicate that stem cells undergo a unique AS pattern and have a different protein expression profile from differentiated cells, giving a new clue that AS switching or AS itself may play a significant role in the processes of differentiation and somatic reprogramming. Indeed, accumulating evidences prove that AS plays critical roles in maintaining pluripotent homeostasis in PSCs. In this review, we summarized recent researches on AS in ESCs and iPSCs, including some distinct AS events in pluripotent cells, and then discussed the new progress on mechanisms for AS in ESCs and iPSCs differentiation and somatic reprogramming.

Aims: A systematic review and meta-analysis were performed to explore the clinical outcome of the transplantation of stem cells from various human tissue sources in cirrhotic patients. Methods: The relevant papers were searched via PubMed, EMBASE, and Cochrane Library databases. Changes in liver function before and after stem cell therapy were evaluated (self-control data). Difference in liver function and incidence of procedure-related complications, hepatocellular carcinoma (HCC), and death between patients undergoing stem cell therapy and conventional treatment were evaluated (case-control data). Results: Of 786 papers initially identified, 31 were included. The sources of stem cell included bone marrow (n=26), umbilical cord (n=3), peripheral blood (n=1), and human fetal liver (n=1). No severe procedure-related complications were reported. According to the meta- analyses of self-control data, model for end-stage liver diseases (MELD) score was significantly reduced at the 3rd-4th and 6th months after stem cell therapy, but this reduction was not statistically significant at the 1st-2nd or 12th postoperative months. Child-Pugh score was also reduced after stem cell therapy, but the reduction was not statistically significant at all follow-up time points. According to the meta-analyses of case-control data, MELD and Child-Pugh scores were not significantly different between treatment and control groups at all follow-up time points. The incidence of HCC was not significantly different between treatment and control groups (odds ratio [OR] to=0.41, P=0.53). The mortality was not significantly different between the two groups (OR=0.48, P=0.20). Conclusion: Stem cell therapy could improve the liver function without any severe procedure-related complications. However, compared with conventional treatment, the benefit of stem cell therapy appeared to be not significant in improving the liver function and survival.

Tumoral angiogenesis is mainly an endothelial cell-mediated process, which has been largely demonstrated to take on a crucial role in tumor growth, invasion, and metastasis. Thus, tumor-associated neovasculature represents a pivotal target in cancer therapy. Several mechanisms take part in the genesis of this pathological vasculature, most notably neoangiogenesis and postnatal vasculogenesis. These processes may also play a critical role in the resistance to antiangiogenic agents, leading to tumor progression. In particular, vasculogenesis is mediated by endothelial progenitor cells (EPCs), which include cellular subpopulations with different functional capacities. EPCs are able to proliferate, migrate, and differentiate into mature endothelial cells (ECs) in response to tumor growth, promoting the “angiogenic switch” and, consequently, inducing the invasion and metastases of cancer cells. Therefore, vasculogenesis mediated by EPCs represents an intriguing therapeutic target, both in early and late stages of cancer progression, thereby working as potential landmark for synthesizing novel and more effective anti-angiogenic drugs. Here, we aim to focus and to summarize several biological features of EPCs and EPC-based therapeutic approach with potential translation in human clinical trials.