The role of BMP4 in adipose-derived stem cell differentiation: A minireview

Abstract

Bone morphogenetic protein 4 (BMP4) is a member of the transforming growth factor beta (TGF-β) superfamily of cytokines responsible for stem cells' commitment to differentiation, proliferation, and maturation. To date, various studies have utilized BMP4 as a chemical inducer for in vitro differentiation of human mesenchymal stem cells (MSCs) based on its potential. BMP4 drives in vitro differentiation of ADSC via TGF-β signaling pathway by interactions with BMP receptors leading to the activation of smad-dependent and smad-independent pathways. The BMP4 signaling pathways are regulated by intracellular and extracellular BMP4 antagonists. Extracellular BMP4 antagonist prevents interaction between BMP4 ligand to its receptors, while intracellular BMP4 antagonist shutdowns the smad-dependent pathways through multiple mechanisms. BMP4 proved as one of the popular differentiation factors to induce ADSC differentiation into cell from mesodermal origin. However, addition of all-trans retinoic acid is also needed in trans-differentiation of ADSC into ectodermal lineage cells. Suggesting that both BMP4 and RA signaling pathways may be necessary to be activated for in vitro trans-differentiation of ADSC.

Keywords: ADSC; BMP4; differentiation; lineage; signaling.

FIGURE 1

BMP4 signaling pathways and its’ regulatory mechanisms in stem cell differentiation: (A) Activation of smad-dependent pathway is initiated when BMP4 dimer binds to BMPR1/2 complex. This interaction activates the phosphorylation of receptor-associated SMADs (SMAD 1/5/8) by BMPR1 to produce R-smads. R-smads then recruit SMAD4 to form Co-smad and translocate into the nucleus leading to downstream signaling. (B) In smad-independent pathway, BMPR1 activates MAP kinase and acts as transcription factors inside the nucleus. Both pathways induce cell commitment and differentiation. (C) BMP4 signaling pathways are regulated by intracellular and extracellular antagonist molecules. Extracellular BMP antagonist (noggin, chordin, follistatin, gremlin and BAMBI) binds to BMP4 dimer ligand and prevent the interaction of BMP4 ligand with its BMP receptors leading to no activation of smad-dependent pathway. On the other hand, intracellular BMP antagonist, known as inhibitory smad (I-smad), shutdown the activated smad-dependent pathway by preventing the phosphorylation of r-smads and block the interaction between R-smads with Co-smads. This schematic was created with BioRender.com.