Current Stem Cell Research & Therapy - Volume 9, Issue 1, 2014

Vascularized composite allotransplantation (VCA) enables surgeons to address complex problems that exceed the possibilities of traditional autologous reconstruction. However, logistical and immunologic challenges currently limit the widespread application of VCA. Recent breakthroughs in the field of stem cells and tissue engineering have direct implications for the advancement of VCA. Specifically, the use of bioreactors may prolong ex vivo allograft survival and enable allograft modulations that mitigate immunogenicity and enhance graft function. Additionally, novel approaches utilizing bioreactor systems for stem cell seeding of vascularized bioscaffolds provide a blueprint for the de novo generation of complex tissues. These promising bioreactor-based strategies have the potential to expand the reconstructive applications of VCA, and could one day allow the fabrication of customized complex tissue grafts.

Liver is a major metabolic organ of the body and is known to comprise of two epithelial cell lineages, namely, hepatocytes and cholangiocytes which are known to originate from hepatoblasts during fetal developing stages. Upon acute injury, the hepatocytes and cholangiocytes undergo cellular division to compensate the loss, however, chronic damage may suppress this proliferative ability and as a consequence hepatic and extra-hepatic stem cells may contribute for liver regeneration. Facultative liver stem cells (oval cells) may emerge, proliferate and contribute in replacing damaged hepatic cells. Similarly, bone marrow and mesenchymal stem cells are also known for contributing in liver regeneration having their ability of self renewal and differentiation. However, a closer look is still required to bridge the existing knowledge gaps between functionality and limitations. Thereby, we have discussed the detailed mechanistic insights of both hepatic and extra-hepatic stem cells including, stem/progenitor cells, adult/fetal hepatocytes, oval cells, bone marrow and mesenchymal stem cells. We have also focused on few in vitro and in vivo studies elucidating therapeutic applications and challenges related to the liver stem cells. We believe that such conversations may provide invaluable contribution for realistic advancement in the state of therapeutic stem-cell transplantation.

Reactive oxygen species (ROS) have been widely considered as critical cellular signaling molecules involving in various biological processes such as cell growth, differentiation, proliferation, apoptosis, and angiogenesis. The homeostasis of ROS is critical to maintain normal biological processes. Increased production of ROS, namely oxidative stress, due to either endogenous or exogenous sources causes irreversible damage of bio-molecules such as DNA, proteins, lipids, and sugars, leading to genomic instability, genetic mutation, and altered gene expression, eventually contributing to tumorigenesis. A great amount of experimental studies in vitro and in vivo have produced solid evidence supporting that oxidative stress is strongly associated with increased tumor cell growth, treatment resistance, and metastasis, and all of which contribute to tumor aggressiveness. More recently, the data have indicated that altered production of ROS is also associated with cancer stem cells (CSCs), epithelial-to-mesenchymal transition (EMT), and hypoxia, the most common features or phenomena in tumorigenesis and tumor progression. However, the exact mechanism by which ROS is involved in the regulation of CSC and EMT characteristics as well as hypoxia- and, especially, HIF-mediated pathways is not well known. Emerging evidence suggests the role of miRNAs in tumorigenesis and progression of human tumors. Recently, the data have indicated that altered productions of ROS are associated with deregulated expression of miRNAs, suggesting their potential roles in the regulation of ROS production. Therefore, targeting ROS mediated through the deregulation of miRNAs by novel approaches or by naturally occurring anti-oxidant agents such as genistein could provide a new therapeutic approach for the prevention and/or treatment of human malignancies. In this article, we will discuss the potential role of miRNAs in the regulation of ROS production during tumorigenesis. Finally, we will discuss the role of genistein, as a potent anti-tumor agent in the regulation of ROS production during tumorigenesis and tumor development.

Human amniotic fluid stem cells (hAFSCs) can be readily isolated from human amniotic fluid and display multi-differentiation potential and immunomodulatory properties. The mechanism of hAFSCs immunoregulation has not been defined. Here, we explore the immunomodulatory effects of hAFSCs derived from human amniotic fluid and evaluate the role of IL-10 and the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) in mediating the immunosuppressive actions of hAFSCs. Flow cytometry showed that hAFSCs were positive for the mesenchymal stem cell markers CD29, CD44, CD105, HLA-ABC, and more than 84% of the hAFSCs were positive for SSEA-4, which is a typical marker of embryonic stem cell (ESCs), and negative for HLA-DR. The RT-PCR and immunostaining results revealed that the multipotent stem cells expressed OCT-4, Nanog, CD44, SOX2 and SSEA-1. In vitro differentiation assays demonstrated that hAFSCs underwent osteogenic differentiation. We examined the immunomodulatory function of hAFSCs using a co-culture system with phorbol 12-myristate 13-acetate (PMA) stimulated peripheral blood mononuclear cells (PBMCs). PBMC proliferation was suppressed by the hAFSCs in a dose-dependent manner. The inhibitory effect was caused by increased IL-10 and IDO induction after co-culture. Neutralizing the IL-10 activity or blocking the function of IDO partially abolished the immunosuppressive action of the hAFSCs. In conclusion, these results suggest that the hAFSCs possess immunomodulatory properties, and IL-10 and IDO are involved in immunosuppression by hAFSCs.

Ewing`s sarcoma (ES) family of tumors (ESFTs) are round cell tumors of bone and soft tissues, afflicting children and young adults. This review summarizes the present findings about ES cancer stem cell (CSC) targeted therapy: prognostic factors, chromosomal translocations, initiation, epigenetic mechanisms, candidate cell of ES origin (Mesenchymal stem cells (MSCs) and Neural crest stem cells (NCSCs)). The ES CSC model, histopathogenesis, histogenesis, pathogenesis, ES mediated Hematopoietic stem progenitor cells (HSPCs) senescence are also discussed. ESFTs therapy is reviewed concerning CSCs, radiotherapy, risk of subsequent neoplasms, stem cell (SC) support, promising therapeutic targets for ES CSCs (CSC markers, immune targeting, RNAi phenotyping screens, proposed new drugs), candidate EWS-FLI1 target genes and further directions (including human embryonic stem cells (hESCs)). Bone marrowderived human MSCs are permissive for EWS-FLI1 expression with transition to ESFT-like cellular phenotype. ESFTs are genetically related to NCSC, permissive for EWS-FLI1 expression and susceptible to oncogene-induced immortalization. Primitive neuroectodermal features and MSC origin of ESFTs provide a basis of immune targeting. The microRNAs profile of ES CSCs is shared by ESCs and CSCs from divergent tumor types. Successful reprogramming of differentiated human somatic cells into a pluripotent state allows creation of patient- and disease-specific SCs. The functional role of endogenous EWS at stem cell level on both senescence and tumorigenesis is a link between cancer and aging. The regulatory mechanisms of oncogenic activity of EWS fusions could provide new prognostic biomarkers, therapeutic opportunities and tumor-specific anticancer agents against ESFTs.

One aim of stem cell-based therapy is to utilize pluripotent stem cells (PSCs) as a supplementary source of cells to repair or replace tissues or organs that have ceased to function due to severe tissue damage. However, PSC-based therapy requires extensive research to ascertain if PSC derivatives are functional without the risk of tumorigenicity, and also do not engender severe immune rejection that threatens graft survival and function. Recently, the suitability of induced pluripotent stem cells applied for patient-tailored cell therapy has been questioned since the discovery of several genetic and epigenetic aberrations during the reprogramming process. Hence, it is crucial to understand the effect of these abnormalities on the immunogenicity and survival of PSC grafts. As induced PSC-based therapy represents a hallmark for the potential solution to prevent and arrest immune rejection, this review also summarizes several up-to-date key findings in the field.