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Review
, 21 (4), 380-392

Pleiotropic Roles of Autophagy in Stem Cell-Based Therapies

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Review

Pleiotropic Roles of Autophagy in Stem Cell-Based Therapies

Vladimir Beljanski et al. Cytotherapy.

Abstract

Stem cells (SCs) have been proven to possess regenerative and immunomodulatory properties and can be used to treat diseases that involve loss of cells due to tissue damage or inflammation. For this approach to succeed, SCs or their derivatives should be able to engraft in the target tissue at least for a short period of time. Unfortunately, once injected, therapeutic SCs will encounter a hostile environment, including hypoxia, lack of nutrients and stromal support, and cells may also be targeted and rejected by the immune system. Therefore, SC's stress-response mechanisms likely play a significant role in survival of injected cells and possibly contribute to their therapeutic efficacy. Autphagy, a stress-response pathway, is involved in many different cellular processes, such as survival during hypoxia and nutrient deprivation, cellular differentiation and de-differentiation, and it can also contribute to their immunovisibility by regulating antigen presentation and cytokine secretion. Autophagy machinery interacts with many proteins and signaling pathways that regulate SC properties, including PI3K/Akt, mammalian target of rapamycin (mTOR), Wnt, Hedgehog and Notch, and it is also involved in regulating intracellular reactive oxygen species (ROS) levels. In this review, we contend that autophagy is an important therapeutic target that can be used to improve the outcome of SC-based tissue repair and regeneration. Further research should reveal whether inhibition or stimulation of autophagy increases the therapeutic utility of SCs and it should also identify appropriate therapeutic regimens that can be applied in the clinic.

Figures

Figure 1:
Figure 1:
Key players in autophagosome formation. mTOR protein complex responds to the metabolic state of the cell via multiple signaling axes. Such signaling molecules sense changes in cellular homeostasis, and, by default, mTOR blocks induction of autophagy. However, increased cellular stress blocks mTOR signaling initiating the pathway, which, in addition to ATG1 kinase requires several other kinases such as PI3K III and VPS34. BECLIN1 is a scaffold protein inhibited by the oncogene BCL2 that inhibits both autophagy and apoptosis initiation. Lipid molecules incorporated into phagophore membrane are not synthesized de-novo but originate in the endoplasmic reticulum (ER). The elongation of autophagosomes is facilitated by formation of ATG12-ATG5-ATG16L protein complex and by LC3-II protein (indicated by green circles) which is lipidated and associated with the autophagosomal membranes. Proper autophagosomes processing also requires ubiquitin-like conjugating enzymes ATG3, ATG7 and ATG10 and protease ATG4 which catalyzes LC3-I to LC3-II conversion. After the membrane enclosure, only ATG12-ATG5-ATG16L1 protein complex dissociates from the autophagosomes - LC3-II remains associated with autophagosomal membrane and is degraded in lysosomes together with other cytoplasmic molecules targeted for degradation. Various small molecules targeting distinct molecules are listed in red.
Figure 2:
Figure 2:
Key aspects of MSC-based therapies that could be improved with autophagy modulation. Upon injection, the cells will likely encounter lack of both nutrients and stromal support, adverse inflammation response, and increased levels of damaged proteins due to increased levels of Reactive Oxygen Species (ROS). Therapeutic modulation of autophagy prior to or during cell administration may offset some or all these adverse effects by preparing MSCs for adverse conditions they will encounter and by facilitating cellular remodeling that may be needed for increased therapeutic effects.

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