Stem cells have the unique capacity to differentiate into many cell types during embryonic development and postnatal growth. Through coordinated cellular behaviors (self-renewal, proliferation, and differentiation), stem cells are also pivotal to the homeostasis, repair, and regeneration of many adult tissues/organs and thus of great importance in regenerative medicine. Emerging evidence indicates that mitochondria are actively involved in the regulation of stem cell behaviors. Mitochondria undergo specific dynamics (biogenesis, fission, fusion, and mitophagy) during stem cell self-renewal, proliferation, and differentiation. The alteration of mitochondrial dynamics, fine-tuned by stem cell niche factors and stress signaling, has considerable impacts on stem cell behaviors. Here, we summarize the recent research progress on (1) how mitochondrial dynamics controls stem cell behaviors, (2) intrinsic and extrinsic factors that regulate mitochondrial dynamics, and (3) pharmacological regulators of mitochondrial dynamics and their therapeutic potential. This review emphasizes the metabolic control of stemness and differentiation and may shed light on potential new applications in stem cell-based therapy.

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Mitochondrial Dynamics: Biogenesis, Fission, Fusion, and Mitophagy in the Regulation of Stem Cell Behaviors

Mesenchymal stem cells (MSCs) are pivotal to tissue homeostasis, repair, and regeneration due to their potential for self-renewal, multilineage differentiation, and immune modulation. Mitochondria are highly dynamic organelles that maintain their morphology via continuous fission and fusion, also known as mitochondrial dynamics. MSCs undergo specific mitochondrial dynamics during proliferation, migration, differentiation, apoptosis, or aging. Emerging evidence suggests that mitochondrial dynamics are key contributors to stem cell fate determination. The coordination of mitochondrial fission and fusion is crucial for cellular function and stress responses, while abnormal fission and/or fusion causes MSC dysfunction. This review focuses on the role of mitochondrial dynamics in MSC commitment under physiological and stress conditions. We highlight mechanistic insights into modulating mitochondrial dynamics and mitochondrial strategies for stem cell-based regenerative medicine. These findings shed light on the contribution of mitochondrial dynamics to MSC fate and MSC-based tissue repair.

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Mitochondrial Dynamics: Fission and Fusion in Fate Determination of Mesenchymal Stem Cells.

Hepatocellular carcinoma is often treated with a combination of doxorubicin and embolization, exposing it to high concentrations and hypoxia. Separation of the possible synergistic effect of this combination in vivo is difficult. Here, treatment with doxorubicin, under hypoxia or normoxia in different liver cancer cell lines, was evaluated. Liver cancer cells HepG2, Huh7, and SNU449 were exposed to doxorubicin, hypoxia, or doxorubicin + hypoxia with different duration. Treatment response was evaluated with cell viability, apoptosis, oxidative stress, and summarized with IC50. The protein profile of a 92-biomarker panel was analyzed on cells treated with 0 or 0.1 µM doxorubicin during 6 or 72 h, under normoxia or hypoxia. Hypoxia decreased viability of HepG2 and SNU499. HepG2 was least and SNU449 most tolerant to doxorubicin treatment. Cytotoxicity of doxorubicin increased over time in HepG2 and Huh7. The combination of doxorubicin + hypoxia affected the cells differently. Normalized protein expression was lower for HepG2 than Huh7 and SNU449. Hierarchical clustering separated HepG2 from Huh7 and SNU449. These three commonly used cell lines have critically different responses to chemotherapy and hypoxia, which was reflected in their different protein expression profile. These different responses suggest that tumors can respond differently to the combination of local chemotherapy and embolization.

Liver Cancer Cell Lines Treated with Doxorubicin under Normoxia and Hypoxia: Cell Viability and Oncologic Protein Profile.

Mounting evidence indicates that circular RNAs (circRNAs) have essential roles in several diseases, including periodontitis. Periodontal ligament stem cells (PDLSCs) exhibit potential for treating periodontitis accompanied by hypoxia. However, it is unclear how circRNA affects the osteogenesis of PDLSCs under hypoxia. In this study, a novel circRNA, hsa_circ_0003489, was found located at the gene for cyclin-dependent kinase 8 (CDK8) and referred to as circCDK8. The expression levels of circCDK8 and hypoxia-inducible factor-1α were significantly increased in periodontitis tissues, and the expression of circCDK8 was further confirmed in a hypoxia model using cobalt chloride (CoCl2 ). Interestingly, the results showed that the expression levels of osteoblast markers (RUNX2, ALP, OCN, and COL1A1) were increased in CoCl2 -treated PDLSCs at 6 and 12 h, but decreased at 24, 48, and 72 h. On the basis of bioinformatics and functional experiments, CoCl2 also induced endoplasmic reticulum stress, autophagy, and apoptosis of PDLSCs; the inhibition of autophagy promoted the osteogenic differentiation of CoCl2 -treated PDLSCs. Furthermore, circCDK8 overexpression induced autophagy and apoptosis through mTOR signaling, and circCDK8 silencing reversed the inhibitory effects of CoCl2 on osteogenic differentiation of PDLSCs. In conclusion, our results indicate that circCDK8 represses the osteogenic differentiation of PDLSCs by triggering autophagy activation in a hypoxic microenvironment. CircCDK8 could be a new therapeutic target of periodontitis.

CircCDK8 regulates osteogenic differentiation and apoptosis of PDLSCs by inducing ER stress/autophagy during hypoxia.

The incidence of periodontitis is very high, and up to 45-50% of people are suffering from periodontitis. Periodontitis is caused by pathogens that invade teeth-supporting tissues such as gingiva, periodontal ligament, and alveolar bone. Pathogens trigger host immune responses characterized by the overproduction of reactive oxygen species (ROS). The development of effective ROS scavengers through nanotechnology has been emerging as a promising strategy for the treatment of periodontitis. Nanomaterial-based antioxidants can effectively scavenge ROS, prevent ROS-mediated tissue damage, and relieve inflammation in periodontitis. This mini-review focuses on the generation of ROS in periodontitis and its molecular mechanism of destroying periodontal tissue. Meanwhile, we summarize the research progress of ROS-scavenging nanomaterials in the treatment of periodontitis and discuss the challenges and prospects of its application.

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ROS-Scavenging Nanomaterials to Treat Periodontitis.

Oxygen deficiency is associated with various oral diseases, including chronic periodontitis, age-related alveolar bone loss, and mechanical stress-linked cell injury from orthodontic appliances. Ne...

CoCl2 induces apoptosis via a ROS-dependent pathway and Drp1-mediated mitochondria fission in periodontal ligament stem cells

Ketogenic diet attenuates post-cardiac arrest brain injury by upregulation of pentose phosphate pathway-mediated antioxidant defense in a mouse model of cardiac arrest.

Tao Li

Papers

CoCl2 induces apoptosis via a ROS-dependent pathway and Drp1-mediated mitochondria fission in periodontal ligament stem cells

Ketogenic diet attenuates post-cardiac arrest brain injury by upregulation of pentose phosphate pathway-mediated antioxidant defense in a mouse model of cardiac arrest.