Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive upper and lower motor neuron (MN) degeneration with unclear pathology. The worldwide prevalence of ALS is approximately 4.42 per 100,000 populations, and death occurs within 3–5 years after diagnosis. However, no effective therapeutic modality for ALS is currently available. In recent years, cellular therapy has shown considerable therapeutic potential because it exerts immunomodulatory effects and protects the MN circuit. However, the safety and efficacy of cellular therapy in ALS are still under debate. In this review, we summarize the current progress in cellular therapy for ALS. The underlying mechanism, current clinical trials, and the pros and cons of cellular therapy using different types of cell are discussed. In addition, clinical studies of mesenchymal stem cells (MSCs) in ALS are highlighted. The summarized findings of this review can facilitate the future clinical application of precision medicine using cellular therapy in ALS.
The mechanism on how extracellular matrix (ECM) cooperates with niche growth factors and oxygen tension to regulate the self-renewal of embryonic germline stem cells (GSCs) still remains unclear. Lacking of an appropriate in vitro cell model dramatically hinders the progress. Herein, using a serum-free culture system, we demonstrated that ECM laminin cooperated with hypoxia and insulin-like growth factor 1 receptor (IGF-1R) to additively maintain AP activity and Oct-4 expression of AP + GSCs. We found the laminin receptor CD49f expression in d2 testicular GSCs that were surrounded by laminin. Laminin and hypoxia significantly increased the GSC stemness-related genes, including Hif-2α, Oct-4, IGF-1R, and CD49f. Cotreatment of IGF-1 and laminin additively increased the expression of IGF-IR, CD49f, Hif-2α, and Oct-4. Conversely, silencing IGF-1R and/or CD49f decreased the expression of Hif-2α and Oct-4. The underlying mechanism involved CD49f/IGF1R-(PI3K/AKT)-Hif-2α signaling loop, which in turn maintains Oct-4 expression, symmetric self-renewal, and cell migration. These findings reveal the additive niche laminin/IGF-IR network during early GSC development.
The role of a YAP-IGF-1R signaling loop in HCC resistance to sorafenib remains unknown.Sorafenib-resistant cells were generated by treating naïve cells (HepG2215 and Hep3B) with sorafenib. Different cancer cell lines from databases were analyzed through the ONCOMINE web server. BIOSTORM-LIHC patient tissues (46 nonresponders and 21 responders to sorafenib) were used to compare YAP mRNA levels. The HepG2215_R-derived xenograft in SCID mice was used as an in vivo model. HCC tissues from a patient with sorafenib failure were used to examine differences in YAP and IGF-R signaling.Positive associations exist among the levels of YAP, IGF-1R, and EMT markers in HCC tissues and the levels of these proteins increased with sorafenib failure, with a trend of tumor-margin distribution in vivo. Blocking YAP downregulated IGF-1R signaling-related proteins, while IGF-1/2 treatment enhanced the nuclear translocation of YAP in HCC cells through PI3K-mTOR regulation. The combination of YAP-specific inhibitor verteporfin (VP) and sorafenib effectively decreased cell viability in a synergistic manner, evidenced by the combination index (CI).A YAP-IGF-1R signaling loop may play a role in HCC sorafenib resistance and could provide novel potential targets for combination therapy with sorafenib to overcome drug resistance in HCC.
Abstract Well-differentiated testicular germ cell tumors (TGCTs) are more drug insensitive and have a poorer prognosis than pluripotent germ cell tumors. However, the mechanism underlying the differentiation regulation of pluripotent seminomas/embryonal carcinomas (ECs) still remains largely unknown. Herein, we demonstrated an important role of SUMO1/sentrin specific peptidase 1 (SENP1) in the sumoylation and stability of the OCT4 protein in the drug sensitivity of hypoxic ECs. Hypoxia decreased the OCT4 protein level, but not the messenger RNA level, in pluripotent ECs. Hypoxic challenge and SUMO1 overexpression increased OCT4 sumoylation and protein instability. A further mutation at the specific OCT4 lysine 123 (HA-OCT4-K123R) effectively suppressed OCT4 sumoylation and protein instability, demonstrating the important role of the specific sumoylation of lysine 123 in OCT4 protein stability under hypoxia. Consistently, overexpression of SUMO1 decreased the endogenous OCT4 half-life in hypoxic NCCIT cells. The band-shift of endogenous sumoylated OCT4 in hypoxic NCCIT cells was demonstrated using Western blot analysis. SENP1 effectively suppressed OCT4 sumoylation and increased OCT4 stability and drug sensitivity in hypoxic NCCIT cells in vitro. Furthermore, overexpression of SENP1 in hypoxic NCCIT cells increased the drug sensitivity in a nude mice model, demonstrating the upstream regulation of SENP1 in OCT4 sumoylation, protein stability, and the drug susceptibility of NCCIT cells. In summary, we demonstrated that the sumoylation regulator, SENP1, positively regulates OCT4 stability and drug sensitivity of pluripotent EC cells through sumoylation. Findings of this study provide insights into the regulation by sumoylation of pluripotent TGCTs differentiation, which has the potential for pharmacological development of effective therapeutic targeting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 423. doi:1538-7445.AM2012-423
Significance Formation of the gas-exchange region of the lung occurs largely postnatally through a process called alveologenesis. Alveolar abnormalities are a hallmark of neonatal and adult chronic lung diseases. Here we report that disruption of Notch signaling in mice, particularly by Notch2, results in abnormal enlargement of the alveolar spaces reminiscent of that seen in chronic lung diseases. We provide evidence that Notch is crucial to mediate cross-talk between different cell layers, including signals such as PDGF for formation of the alveoli and maintenance of the integrity of the conducting airways.
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