Current Stem Cell Research & Therapy - Volume 11, Issue 3, 2016

This review summarizes recent breakthroughs in studies regarding proliferation of adult stem cells which complement and extend our knowledge to various aspects of cell biology and signal pathways. In recent years, many interesting results and discoveries were achieved regarding the proliferative properties of stem cells. In vitro expansion of stem cells may benefit from high proliferation rates, which can produce a large amount of cells to regenerate tissue defects. Meanwhile, optimizing the culture conditions for stem cell propagation is helpful in maintaining the pluripotency and differentiation potential of stem cells, which are critical for tissue engineering and regenerative medicine. Additionally, understanding the proliferation of stem cells may help us to uncover new mechanisms of drug resistance, since stem cells are believed to play an important role in drug resistance. In this review, we focus on signaling pathways regulating the proliferation of various stem cells isolated from adult tissues. We also emphasize the significance of stem cells proliferation in cell research, as well as rapid propagation of adult stem cells for regenerative medicine.

In recent years, beneficial effects of various ligands of three peroxisome-proliferatoractivated receptor (PPAR) isoforms (α, β, γ) have been reported in neurodegenerative diseases through delaying the onset and progression of diseases, reducing lesion size and improving functional recovery. Neural stem cells (NSCs) are assumed as a promising strategy for the treatment of human neurodegenerative diseases. PPARs are supposed to be one group of the key regulators of fate decisions in25882852 neural stem cells during development and adulthood, through their impact on the target genes involving cell proliferation, death and differentiation. The neuroprotective role of PPARs is suggested to be closely associated with the inflammation control and regenerative function of NSCs. Nevertheless, the molecular mechanisms remain to be elucidated. Here, we review the current knowledge about the beneficial role of PPARs in NSC development and neurogenesis and attempt to discuss the underlying mechanisms.

Mesenchymal stem cells (MSCs) have the self-renewal ability and the ability to produce multiple differentiation. Elucidating the genetic circuits that govern MSC self-renewal and differentiation is necessary to improve our comprehension of MSCs and their role in regenerative medicine. microRNAs (miRNAs) play important roles in the regulation of transcription, and are strongly linked with MSCs regarding the maintenance of pluripotency properties. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormonereceptor family. Interestingly, PPARs not only regulate glucose metabolism and lipidhomeostasis, but also contribute to cell proliferation, cell differentiation, and cell apoptosis. The aim of the present review was to provide an insight into the roles of miRNAs and PPARs in the differentiation of MSCs. Understanding the miRNA signature interactions in conjunction with the role of PPARs is critical for the development of improved strategies to regulate the differentiation of MSCs.

The peroxisome proliferator-activated receptor –γ (PPARγ) has been identified in a wide range of cancers, including brain, breast, colon, stomach and lung cancers. It belongs to the thyroid/ steroid hormone receptors superfamily. Binding with their special ligands, PPARγ plays important roles in regulating transcription of their target genes. PPARγ activation suppresses the growth of the tumor cells, implicating the anti-tumor potential of PPARγ ligand. Tumors in the nervous system are among the most devastating cancers. This review highlights key advances in understanding the effects of PPARγ ligands in the treatment of tumors in the nervous system.

Mesenchymal stem cells (MSCs) arise from a variety of tissues, including bone marrow and adipose tissue and, accordingly, have the potential to differentiate into multiple cell types, including osteoblasts and adipocytes. Research on MSCs to date has demonstrated that a large number of transcription factors and ectocytic or intrastitial signaling pathways regulate adipogenic and osteogenic differentiation. A theoretical inverse relationship exists in adipogenic and osteogenic lineage commitment and differentiation, such that signaling pathways induce adipogenesis at the expense of osteogenesis and vice versa. For example, peroxisome proliferator-activated receptor γ(PPARγ), which belongs to the nuclear hormone receptor superfamily of ligand-activated transcription factors, is known to function as a master transcriptional regulator of adipocyte differentiation, and inhibit osteoblast differentiation. Moreover, recent studies have demonstrated that inducers of osteogenic differentiation, such as bone morphogenetic protein (BMP) and Wnt, inhibit the function of PPARγ transactivation during MSC differentiation towards adipocytes through a variety of mechanisms. To illustrate this, the canonical Wnt/β-catenin pathway represses expression of PPARγ mRNA, whereas the noncanonical Wnt pathway activates histone methyltransferases that inhibit PPARγ transactivation via histone H3 lysine 9 (H3K9) methylation of its target genes. The role of microRNAs (miRNAs) in adipogenesis and osteoblastogenesis is garnering increased attention, and studies in this area have shed light on the integration of miRNAs with Wnt signaling and transcription factors such as Runx2 and PPARγ. This review summarizes our current understanding of the mechanistic basis of these signaling pathways, and indicates future clinical applications for stem cell-based cell transplantation and regenerative therapy.

Cancer stem cells (CSCs) are cancer cells with characteristics of stem cells, especially the ability to arise to all types of cell in a particular cancer tissue. With the capacity to generate multiple types of cancer cells, CSCs are proposed as primary impetus for tumor initiation and metastases and are suggested as potential therapeutic targets for anti-cancer treatment. Peroxisome-proliferatoractivated receptors (PPARs) are a subset of multifunctional transcription factors which play a pivotal role in cancer development and tumorigenesis. PPARs are also reported to be involved in the modulation of the epithelial-mesenchymal transition (EMT) process in CSC initiation and in the regulation of CSC functions. However, the exact mechanisms remain unknown. Herein, we review the latest evidence on the regulatory effects and mechanisms of PPARs in CSC formation and function, and evaluate the prospects of PPARs as a target for cancer treatment.

Mesenchymal stem cells (MSCs) are multipotent progenitors that have the abilities of selfrenewal and multiple direction differentiation. The osteogenic potential of MSCs holds great promise for bone defect repair and bone disease treatment. For a long time studies about osteogenic differentiation of MSCs have emphasized on the effect of extrinsic regulators and the corresponding transcription factors controlling cell fate. In fact, cell fate is determined by lineage specific gene expression that is regulated more specifically by epigenetic mechanism. Over the last decade, some progress has been made in epigenetic researches of MSCs osteogenic differentiation. DNA methylation, histone modifications and microRNA (miRNA) are all verified important mechanisms regulating MSCs differentiation. Epigenetic regulation might provide novel treatment targets for promoting bone formation. In this review, we will summarize the recent advance about the epigenetic mechanism that control MSCs commitment to osteoblasts and the potential clinical application of MSCs epigenetics in future.

The pluripotent mesenchymal stem cells (MSC) are common precursors to adipocytes and osteoblasts. Large numbers of extracellular and intracellular signals and transcription factors moderate adipogenesis and osteoblastogenesis. Importantly, between adipogenic and osteogenic lineage commitment and differentiation, differentiation of MSCs into one lineage will inhibit their differentiation toward the other lineage. This balance is regulated by numerous signaling pathways. As we know, the peroxisome-proliferator-activated receptor-γ (PPAR-γ) and Wnt/β-catenin pathway are regarded as the master moderators of adipogenesis and osteogenesis. Moreover, governing the differentiation of MSCs to adipogenesis and osteoblastogenesis has significant implications in diverse areas of human health, from obesity to regenerative medicine to osteoporosis. Rivalry roles have been reported of the two pathways since the downstream products activated by Wnt-5a repress PPAR-γ transactivation through the H3K9 histone methyltransferase protein complexes. This review will discuss the inductive and inhibitive role of PPAR-γ in adipogenesis and osteoblastogenesis respectively, as well as the canonical Wnt/β-catenin pathway.

Sharing the same precursor cell lineage located in the bone marrow, mesenchymal stroma/stem cells (MSCs), osteoblasts and adipocytes have a reciprocal relationship in differentiation and function. The nuclear transcription factor peroxisomeproliferator- activated receptor-gamma (PPAR-γ) has been found expressed in both osteoblasts and adipocytes, as well as in MSCs, suggesting its crucial role in regulating adipocyte formation and osteoblast development. It has been observed in animal models that upregulated PPAR-γ activity results in bone loss where marrow adiposity is facilitated, while downregulated PPAR-γactivity leads to bone mass elevation. Evidence suggests that the dual function of PPAR-γ in either anti-osteoblastic or pro-adipocytic aspects is determined by its ligand. Furthermore, various cytokines and extracellular signaling pathways are involved in the transactivation of PPAR-γ, which can trigger the adipogenesis/osteoblastogenesis switch. PPAR-γ, therefore, shows tremendous potential in novel strategies for bone tissue engineering and clinical application. This review summarizes the regulatory function of PPAR-γ in MSC differentiation, as well as the cytokine and extracellular signaling pathways participating in the cross-talk between adipogenesis and osteoblastogenesis.

Angiogenesis is a complex process in which capillaries are produced from blood vessels that already exists.. Endothelial cells (ECs) and endothelial progenitor cells (EPCs) are pivotal for this process and for the maintenance/restorage of the endothelium. Decreased numbers and dysfunction of these cells have been related to growing cardiovascular risks. Peroxisome-proliferator-activated receptor (PPAR) is a large family of nuclear receptors, characterized by three isotypes: α, β and γ. Numerous studies have shown that PPAR activation is involved in the pathology of a wide range of cardiovascular diseases and has a role in endothelial function, thrombosis and inflammation, etc., suggesting that PPAR agonists may be good candidates to treat the cardiovascular disease. However, controversial results exist on whether this nuclear receptor is inductive or depressive in the process of angiogenesis. Herein, this review will provide a detailed discussion of the up-to-date investigation of the role of PPARs in angiogenesis, with particular reference to their effects on angiogenesis-related cells—i.e., ECs, EPCs, vascular smooth-muscle cells (VSMCs), macrophages and endometrial cells—and will discuss the current and potential future applications of PPAR activators.

Peroxisome proliferator-activated receptor γ (PPARγ) is a versatile member of the ligandactivated nuclear hormone receptor superfamily of transcription factors, with expression in several different cell lines, especially in the digestive system. After being activated by its ligand, PPARγ can suppress the growth of oral, esophageal, gastric, colorectal, liver, biliary, and pancreatic tumor cells, suggesting that PPARγ ligand is a potential anticancer agent in PPARγ-expressing tumors. This review highlights key advances in understanding the effects of PPARγ ligands in the treatment of tumors in the digestive system.

Obesity, which is a key risk for the development of hyperglycemia, hypertension, hyperlipidemia and insulin resistance and is totally referred to as the metabolic disorders, has aroused people’s great attention because of its alarming increase rate around the world. It is widely known that the occurrence of obesity can be attributed to both environmental and genetic factors. Peroxisome proliferators- activated receptor (PPAR), a member of ligand-dependent receptor, is one of the important genetic factors. PPAR includes three isoforms: PPAR-α, PPAR- β and PPAR- γ, all of which are exerting critical influences on the maintenance of the metabolism of saccharides, lipids and proteins. PPAR-γ is of great importance in the regulation of adipogenesis; in addition, it is essential in the prevention of adiposis and the treatment of 2-diabetes mellitus. In this review, we focus on giving a brief introduction about PPAR family, the indispensible function of PPAR-γ in adipogenesis and the inseparable relationship between PPAR-γ and obesity, deriving from the understanding of how these receptors activated will provide windows of opportunities for the treatment of obesity and associated metabolism syndromes.

Regenerative medicine plays an indispensable role in modern medicine and many trials and researches have therefore been developed to fit our medical needs. Tissue engineering has proven that adipose tissue can widely be used and brings advantages to regenerative medicine. Moreover, a trait of adipose stem cells being isolated and grown in vitro is a cornerstone to various applications. Since the adipose tissue has been widely used in regenerative medicine, numerous studies have been conducted to seek methods for gaining more adipocytes. To investigate molecular mechanism for adipocyte differentiation, peroxisome proliferator-activated receptor (PPAR) has been widely studied to find out its functional mechanism, as a key factor for adipocyte differentiation. However, the precise molecular mechanism is still unknown. This review thus summarizes recent progress on the study of molecular mechanism and role of PPAR in adipocyte differentiation.