The 9th Pan Pacific Symposium on Stem Cell and Cancer Research (PPSSC) was held in Taichung, Taiwan, on May 14–16, 2016. There were five themes of the 9th PPSSC, which included (a) pluripotent stem cells and mesenchymal stem cells: frontier research, (b) engineered T-cell therapies: CAR-T strategies in cancer, (c) gene editing of iPSCs for diseases, (d) cancer and new drug development, and (e) bioengineering and biomaterial applications in neuroscience. In this special issue, we highlight some important topics from this symposium, with a special emphasis on new drugs and cell precision therapies for unmet medical needs.
Targets for Cells and New Drug Development
In order to fulfill unmet medical needs, precision therapy may be used to advocate for designing new drugs and cell therapies. Gene and molecular targets are important for developing these new therapies. In this issue, four possible targets were pointed out. The first one is transforming growth factor-β (TGF-β), which may be targeted in precision therapy for neurodegenerative diseases. Li et al. reviewed the molecular mechanisms and activated signaling pathway that affect TGF-β and promote neuroregeneration. The activation of this signaling pathway can regulate neurite outgrowth, scar formation, and neurotrophic factor responses, thereby modulating the behavior of neurons and glial cells.
The second target highlighted is glycogen synthase kinase-3β (GSK-3β). Zhao et al. found that inhibition of GSK-3β resulted in neuroprotection and regeneration in an animal model of hemorrhagic stroke. The authors concluded that inhibition of this protein allows for increased activation of the vital Wnt/β-catenin pathway, which plays a key role in several processes that are essential to brain function and neural repair. Granulocyte colony stimulating factor (G-CSF) was also found to have neuroprotective effects for Parkinson's patients in a clinical study by Tsai et al. Repeated injections of G-CSF for early stage Parkinson's patients slowed disease progression, which the authors attribute to the factor's inherent anti-inflammatory effects and ability to stimulate trophic factor production.
The fourth target involves technology and tissue engineering of cartilage. Lu et al. studied the mechanistic target of rapamycin (mTOR) signaling pathway and its downstream effector, S6Kinase (S6K), on the chondrogenic differentiation of mesenchymal stem cells (MSCs) in 3D chitosan film culture. The results showed that the mTOR/S6 signaling pathway was activated and upregulated within 2 to 7 days after culturing MSCs in the 3D chitosan film system and that this led to better chondrocyte differentiation and cartilage formation.
The last target is important in new drug development for cancer therapy. The pre-S2 gene is involved in the development of hepatocellular carcinoma (HCC). Teng et al. reviewed studies that found that patients with chronic hepatitis B virus (HBV) infection had a risk of developing HCC, especially patients with a pre-S2 mutation. On the basis of these findings, the authors suggest that pre-S2 may be a viable target for new drug development.
Precision Therapies Developed From Cell Therapy and New Drug Research
The combination of translational research and precision therapy has led to the development of new cell therapies and new drugs. Seven new entities are described in this special issue. MSCs are the most widely used cells for clinical trials in the world. Park et al. conducted a preclinical study using MSCs to treat murine neonatal intraventricular hemorrhage (IVH) and showed that there were beneficial effects when using MSCs for this condition. Translation of this approach to a clinical study using MSCs for IVH will necessitate identifying the most optimal source of MSCs, the best administration route, the timing of treatment, and the optimal dose.
Adipose tissue is one of the most abundant sources of stem cells in the human body. Lin et al. conducted a pre-clinical study using human adipose tissue-derived stem cells (ADSCs) to treat an animal model of liver cirrhosis. The important methods employed involved harvesting subcutaneous fat tissue, culturing and expanding ADSCs, studying cell dynamics and toxicology, and assessing chromosome stability in animals. With these data, a phase I/IIa trial on cirrhosis of the liver was approved by the Taiwan Food and Drug Administration (TFDA) and will be conducted with six patients in Taiwan.
Yamashita et al. generated induced neural stem cells (iNSCs) from somatic cells and directly injected them into the striatum of stroke animals. They found that iNSCs could survive and differentiate into glial cells, which resulted in beneficial effects in terms of the survival rate and functional recovery at 8 months after therapy. In addition to cells, neural stem cell-conditioned medium (NSC-M) was used to treat spinal cord injury (SCI). Cheng et al. found that NSC-M administered systemically could improve motor function and cord lesion healing by reducing inflammatory cytokines in lesion sites and inducible nitric oxide synthase (iNOS) expression in the spleens of mice modeled with SCI.
These studies highlight the importance of cell therapy for addressing a litany of conditions. Cell therapy is considered a modern medicine that may address unmet medical needs. The TFDA considers cell therapy to be either a medical practice or a medicinal product. Cell therapy regulation was gradually revised to be much more flexible in an effort to make cell therapy a more expedient, personalized treatment for rare and fatal diseases. The evolution of TFDA regulations on cell therapy is discussed in an article by Chen et al.
Other than drugs, exercise is a natural way to enhance the levels of endogenous stem cells and rejuvenating trophic factors in the body. Chan et al. reported that Qigong exercise reduced symptoms of depression in women with chronic fatigue syndrome (CFS), which may be attributable to exercise-mediated enhancement of adiponectin and hippocampal neurogenesis. Tsai et al. report on another phase I/IIa trial that was conducted using allogeneic AD-MSCs for patients with spinocerebellar ataxia. One patient with multiple system atrophy–-cerebellar type–-was also tested. At the 1-year follow-up, results showed that intravenous systemic transplantation of AD-MSCs for cerebellar degeneration patients was safe. The authors concluded that a phase IIb clinical trial should be conducted.
Fabry disease (FD), α-galactosidase A (GLA) deficiency disease, clinically presents as a progressive cardiovascular dysfunction due to an intracellular accumulation of globotriaosylceramide (Gb3).
Tseng et al. investigated the pathological signaling pathway associated with FD using blood-derived induced pluripotent stem cells (iPSCs). They further differentiated iPSCs into endothelial cells and found that Gb3 accumulation could suppress superoxide dismutase 2 (SOD2) production, increase reactive oxygen species (ROS) formation, enhance AMP-activated protein kinase (AMPK) activity, and, finally, lead to vascular endothelial dysfunction, indicating that mitochondrial ROS may be a target for treating FD.
This special PPSSC issue of Cell Transplantation contains the aforementioned articles, which expound upon the existing body of knowledge pertaining to stem cells and cancer research. We appreciate the contributions of the authors who shared their valuable data and insight. We look forward to another successful meeting of the 10th PPSSC, which will be held on April 15–17, 2017 in Hualien, Taiwan.