Autophagy, Mesenchymal Stem Cell Differentiation, and Secretion

Abstract

Mesenchymal stem cells (MSC) are multipotent cells capable to differentiate into adipogenic, osteogenic, and chondrogenic directions, possessing immunomodulatory activity and a capability to stimulate angiogenesis. A scope of these features and capabilities makes MSC a significant factor of tissue homeostasis and repair. Among factors determining the fate of MSC, a prominent place belongs to autophagy, which is activated under different conditions including cell starvation, inflammation, oxidative stress, and some others. In addition to supporting cell homeostasis by elimination of protein aggregates, and non-functional and damaged proteins, autophagy is a necessary factor of change in cell phenotype on the process of cell differentiation. In present review, some mechanisms providing participation of autophagy in cell differentiation are discussed.

Keywords: autophagy; differentiation; immunomodulation; mesenchymal stem cells; signal transduction.

Figure 1

Autophagy signaling. The inhibition of mTORC1 by Rapamycin or AMPK abolishes mTORC1-dependent suppression of ULK1/2 activity and thereby triggers autophagy. Activation of VPS34 results in synthesis of PI3P necessary for phagophore formation. ATG12 and LC3 conjugation systems are involved in elongation and closure of autophagosome membrane. SQSTM1 as well other autophagy receptors, transfer polyubiquitilated cargo into autophagosome. Autophagosome fuses with lysosome following by degradation of content with lysosomal enzymes. Abbreviations used: ULK, Unk-51 autophagy activating kinase; FIP-200, FAK family kinase interacting protein of 200 kDa; BCN1, Beclin 1; VPS34, vacuolar protein sorting 34, class III PI3 kinase; SQSTM1, sequestosome 1; LC3, microtubule-associated proteins 1A/1B light chain 3B.

Figure 2

Relationship between autophagy and intracellular signaling participating in MSC differentiation. (A) adipogenesis transcription factor C/EBPβ activates proteinase ATG4b, which induces LC3 maturation. LC3II binds factors Klf 2/3 and transfers them into autolysosome, thereby eliminating PPARγ suppression by Klfs [69]. (B) LC3II and SQSTM1 perform autolysosomal degradation of Disheveled (Dvl) and β-catenin. This effect antagonizes SQSTM1 suppression by Wnt/β-catenin signaling [71,72]. (C) autophagy is a necessary factor of MSC differentiation; Wnt and Notch weaken adipogenesis and reinforce osteogenesis. The existence of selective relationships between autophagy and cell signaling creates an opportunity to regulate efficiency of MSC differentiation as a factor of tissue repair.