Elsevier

Differentiation

Volume 92, Issues 1–2, July–August 2016, Pages 41-51
Differentiation

Review article
Key transcription factors in the differentiation of mesenchymal stem cells

https://doi.org/10.1016/j.diff.2016.02.005Get rights and content

Abstract

Mesenchymal stem cells (MSCs) are multipotent cells that represent a promising source for regenerative medicine. MSCs are capable of osteogenic, chondrogenic, adipogenic and myogenic differentiation. Efficacy of differentiated MSCs to regenerate cells in the injured tissues requires the ability to maintain the differentiation toward the desired cell fate. Since MSCs represent an attractive source for autologous transplantation, cellular and molecular signaling pathways and micro-environmental changes have been studied in order to understand the role of cytokines, chemokines, and transcription factors on the differentiation of MSCs. The differentiation of MSC into a mesenchymal lineage is genetically manipulated and promoted by specific transcription factors associated with a particular cell lineage. Recent studies have explored the integration of transcription factors, including Runx2, Sox9, PPARγ, MyoD, GATA4, and GATA6 in the differentiation of MSCs. Therefore, the overexpression of a single transcription factor in MSCs may promote trans-differentiation into specific cell lineage, which can be used for treatment of some diseases. In this review, we critically discussed and evaluated the role of transcription factors and related signaling pathways that affect the differentiation of MSCs toward adipocytes, chondrocytes, osteocytes, skeletal muscle cells, cardiomyocytes, and smooth muscle cells.

Introduction

Mesenchymal stem cells (MSCs) are multipotent stem cells that are capable of self-renewing and differentiating into functional cell types. The ease of isolation, the high migratory capacity, the relatively high expansion rates, and the ability to avoid the allogeneic responses after transplantation (Chen et al., 2004, Fouillard et al., 2007, Le Blanc and Ringden, 2005, Ripa et al., 2007, Sekiya et al., 2002) make them attractive candidates in regenerative medicine. Over the last few years, MSCs have been isolated from various tissues and organs including adipose tissue, bone marrow, placental tissue, umbilical cord blood, the testes, the liver, the pancreas, the spleen, amniotic fluid, menstrual blood, dental pulp, the dermis and the lung (De Coppi et al., 2007, Guan et al., 2006, in't Anker et al., 2003, Kruse et al., 2006, Meng et al., 2007, Pierdomenico et al., 2005, Ringe et al., 2008, Sabatini et al., 2005, Sellheyer and Krahl, 2010). They are characterized by their spindle shaped morphology and their ability to differentiate in vitro into adipocytes, chondrocytes and osteocytes. Previous reports suggest that there is no single specific marker to distinguish MSCs from other cells that exhibit similar fibroblastic characteristics. Hence, these cells are immunophenotypically characterized by positive and negative expression of multiple surface antigens. MSCs express surface antigens such as CD44, CD73, CD29, CD90 and CD105 and lack hematopoietic and endothelial markers such as CD11, CD14, CD31, CD34 and CD45 (Haynesworth et al., 1992, Lodie et al., 2002, Suva et al., 2004). In vitro, MSCs usually grow as a monolayer culture in a medium containing 10% fetal bovine serum and l-glutamine.

The multi-lineage differentiation of MSCs has been extensively studied in vitro and in vivo since their first discovery. These studies have demonstrated that MSCs have the potential to differentiate into several mesoderm-type lineages, including myogenic, adipogenic, osteogenic and chondrogenic lineages (Fig. 1).

During the differentiation of MSCs toward a specific cell type, there are a multitude of stimuli and inhibitors that play important roles in the initial commitment and later stages of differentiation. The differentiation of MSCs into specific mature cell types is controlled by various cytokines, growth factors, extracellular matrix molecules, and transcription factors (TFs). In vitro, the differentiation of MSCs requires certain inducers including some growth factors (Table 1).

To date, many studies have shown that transcription factors can affect the differentiation of MSCs toward different mature cell types. Through the activation of transcription factors, the effect may occur by upregulating the expression of genes responsible for induction and progression of specific-cell type differentiation. In the following sections, we will discuss the characteristics and function of various transcription factors that affect the differentiation of MSCs (isolated from different sources) toward adipocytes, chondrocytes, osteocytes, skeletal muscle cells, cardiomyocytes, and smooth muscle cells.

Section snippets

Osteogenic differentiation

Differentiation of MSCs toward osteocytes is induced in vitro by incubating a monolayer of MSCs with a differentiation medium containing β-glycerophosphate, dexamethasone, ascorbic acid-2-phosphate and combinations of transforming growth factor-beta (TGF-β), bone morphogenetic proteins (BMPs) and vitamin D3 (Friedenstein et al., 1987, Okamoto et al., 2002). At the molecular level, interactions between hormones and transcription factors control the differentiation of MSCs into osteocytes. The

Chondrogenic differentiation

In vitro, chondrogenic differentiation of MSCs is induced by a medium supplemented with ascorbic acid phosphate, dexamethasone, bovine serum albumin, linoleic acid, sodium pyruvate, transferrin, selenous acid, proline, l-glutamine, and TGF- β1 (Okamoto et al., 2002, Sottile et al., 2002, Suva et al., 2004). During differentiation, the morphology of MSCs changes from a fibroblast-like morphology into a round shape. Transcription factors play an important role in the regulation of the gene

Adipogenic differentiation

Adipogenic differentiation of MSCs is stimulated by the incubation of MSCs in a medium containing 3-isobutyl-1-methyl-xanthine, insulin, indomethacin, triiodothyronine, Asc-2-P, basic FGF, and the glucocorticoid dexamethasone (Suva et al., 2004, Zhang et al., 2009). The differentiation of MSCs into adipocytes results in the accumulation of lipids in intracellular vacuoles (Prawitt et al., 2008). The inhibition or activation of some transcription factors is vital to the cellular commitment of

Skeletal muscle cells

In recent years, many studies have reported that MSCs possess the ability to differentiate into skeletal muscle cell lineage when treated with the demethylating agent 5-azacytidine (Jackson et al., 2007, Rowlands et al., 2008). Myogenic differentiation has also been promoted by co-culturing MSCs with skeletal myocytes, neonatal fibroblasts, and neonatal cardiomyocytes (Lee et al., 2005, Ramkisoensing et al., 2011). The inhibition or activation of some transcription factors is vital to the

Conclusion

Among cell types, MSCs are a powerful candidate for regenerative medicine, and for the study of cellular differentiation. They represent an attractive cell source for transplantation because they can be isolated from different tissues. In addition to their ability to differentiate into adipocytes, chondrocytes, osteocytes, smooth muscle cells, endothelial cells, and cardiomyocytes, MSCs are capable of differentiating into additional cell lineage such as neurons and hepatocytes (Pacary et al.,

Acknowledgments

The authors thank Dane Marvin for providing writing assistance and proof reading the article. This work was supported by research Grants R01 HL116042, R01 HL112597, and R01 HL120659 to DK Agrawal from the National Heart, Lung and Blood Institute, National Institutes of Health, USA. The content of this review article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Sami Almalki is financially supported by

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