2018 Vol. 9, No. 3

Lung regeneration is the major challenge of modern
medicine. In this issue, Ma et al. identified a previously
unknown population of adult human lung stem cells, which
locates at the basal layer of airway epithelium and could be
marked by SOX9 gene expression. Culture and orthotopic
transplantation of such cells generated functional human
alveoli and bronchioles in mouse model. In a pilot clinical trial,
after autologous transplantation of such cells, two patients with
chronic lung diseases demonstrated recovery of pulmonary
structure and function. This is the fi rst evidence showing that
human lung tissue could be regenerated by adult stem cell
transplantation. The cover picture illustrated the re-growth of
“respiratory tree”.
Gene editing using CRISPR/Cas9: implications for dual-use and biosecurity
Diane DiEuliis, James Giordano
2018, 9(3): 239-240. doi: 10.1007/s13238-017-0493-4
Lian-Cang Xu: the founder of management psychology in China
Jing Li, Yong-Kang Lu
2018, 9(3): 241-243. doi: 10.1007/s13238-017-0419-1
First stem cell transplantation to regenerate human lung
Si Wang, Jun Wu, Guang-Hui Liu
2018, 9(3): 244-245. doi: 10.1007/s13238-017-0498-z
RIG-I: a multifunctional protein beyond a pattern recognition receptor
Xiao-xiao Xu, Han Wan, Li Nie, Tong Shao, Li-xin Xiang, Jian-zhong Shao
2018, 9(3): 246-253. doi: 10.1007/s13238-017-0431-5
It was widely known that retinoic acid inducible gene I (RIG-I) functions as a cytosolic pattern recognition receptor that initiates innate antiviral immunity by detecting exogenous viral RNAs. However, recent studies showed that RIG-I participates in other various cellular activities by sensing endogenous RNAs under different circumstances. For example, RIG-I facilitates the therapy resistance and expansion of breast cancer cells and promotes T cell-independent B cell activation through interferon signaling activation by recognizing non-coding RNAs and endogenous retroviruses in certain situations. While in hepatocellular carcinoma and acute myeloid leukemia, RIG-I acts as a tumor suppressor through either augmenting STAT1 activation by competitively binding STAT1 against its negative regulator SHP1 or inhibiting AKT-mTOR signaling pathway by directly interacting with Src respectively. These new findings suggest that RIG-I plays more diverse roles in various cellular life activities, such as cell proliferation and differentiation, than previously known. Taken together, the function of RIG-I exceeds far beyond that of a pattern recognition receptor.
T-cell receptor-engineered T cells for cancer treatment: current status and future directions
Yu Ping, Chaojun Liu, Yi Zhang
2018, 9(3): 254-266. doi: 10.1007/s13238-016-0367-1
T-cell receptor (TCR)-engineered T cells are a novel option for adoptive cell therapy used for the treatment of several advanced forms of cancer. Work using TCRengineered T cells began more than two decades ago, with numerous preclinical studies showing that such cells could mediate tumor lysis and eradication. The success of these trials provided the foundation for clinical trials, including recent clinical successes using TCRengineered T cells to target New York esophageal squamous cell carcinoma (NY-ESO-1). These successes demonstrate the potential of this approach to treat cancer. In this review, we provide a perspective on the current and future applications of TCR-engineered T cells for the treatment of cancer. Our summary focuses on TCR activation and both pre-clinical and clinical applications of TCR-engineered T cells. We also discuss how to enhance the function of TCR-engineered T cells and prolong their longevity in the tumor microenvironment.
Research Articles
Regeneration of functional alveoli by adult human SOX9+ airway basal cell transplantation
Qiwang Ma, Yu Ma, Xiaotian Dai, Tao Ren, Yingjie Fu, Wenbin Liu, Yufei Han, Yingchuan Wu, Yu Cheng, Ting Zhang, Wei Zuo
2018, 9(3): 267-282. doi: 10.1007/s13238-018-0506-y
Irreversible destruction of bronchi and alveoli can lead to multiple incurable lung diseases. Identifying lung stem/progenitor cells with regenerative capacity and utilizing them to reconstruct functional tissue is one of the biggest hopes to reverse the damage and cure such diseases. Here we showed that a rare population of SOX9+ basal cells (BCs) located at airway epithelium rugae can regenerate adult human lung. Human SOX9+ BCs can be readily isolated by bronchoscopic brushing and indefinitely expanded in feeder-free condition. Expanded human SOX9+ BCs can give rise to alveolar and bronchiolar epithelium after being transplanted into injured mouse lung, with air-blood exchange system reconstructed and recipient's lung function improved. Manipulation of lung microenvironment with Pirfenidone to suppress TGF-β signaling could further boost the transplantation efficiency. Moreover, we conducted the first autologous SOX9+ BCs transplantation clinical trial in two bronchiectasis patients. Lung tissue repair and pulmonary function enhancement was observed in patients 3-12 months after cell transplantation. Altogether our current work indicated that functional adult human lung structure can be reconstituted by orthotopic transplantation of tissue-specific stem/progenitor cells, which could be translated into a mature regenerative therapeutic strategy in near future.
Targeted elimination of mutant mitochondrial DNA in MELAS-iPSCs by mitoTALENs
Yi Yang, Han Wu, Xiangjin Kang, Yanhui Liang, Ting Lan, Tianjie Li, Tao Tan, Jiangyun Peng, Quanjun Zhang, Geng An, Yali Liu, Qian Yu, Zhenglai Ma, Ying Lian, Boon Seng Soh, Qingfeng Chen, Ping Liu, Yaoyong Chen, Xiaofang Sun, Rong Li, Xiumei Zhen, Yang Yu, Xiaoping Li, Yong Fan
2018, 9(3): 283-297. doi: 10.1007/s13238-017-0499-y
Mitochondrial diseases are maternally inherited heterogeneous disorders that are primarily caused by mitochondrial DNA (mtDNA) mutations. Depending on the ratio of mutant to wild-type mtDNA, known as heteroplasmy, mitochondrial defects can result in a wide spectrum of clinical manifestations. Mitochondria-targeted endonucleases provide an alternative avenue for treating mitochondrial disorders via targeted destruction of the mutant mtDNA and induction of heteroplasmic shifting. Here, we generated mitochondrial disease patient-specific induced pluripotent stem cells (MiPSCs) that harbored a high proportion of m.3243A>G mtDNA mutations and caused mitochondrial encephalomyopathy and stroke-like episodes (MELAS). We engineered mitochondrial-targeted transcription activator-like effector nucleases (mitoTALENs) and successfully eliminated the m.3243A>G mutation in MiPSCs. Off-target mutagenesis was not detected in the targeted MiPSC clones. Utilizing a dual fluorescence iPSC reporter cell line expressing a 3243G mutant mtDNA sequence in the nuclear genome, mitoTALENs displayed a significantly limited ability to target the nuclear genome compared with nuclear-localized TALENs. Moreover, genetically rescued MiPSCs displayed normal mitochondrial respiration and energy production. Moreover, neuronal progenitor cells differentiated from the rescued MiPSCs also demonstrated normal metabolic profiles. Furthermore, we successfully achieved reduction in the human m.3243A>G mtDNA mutation in porcine oocytes via injection of mitoTALEN mRNA. Our study shows the great potential for using mitoTALENs for specific targeting of mutant mtDNA both in iPSCs and mammalian oocytes, which not only provides a new avenue for studying mitochondrial biology and disease but also suggests a potential therapeutic approach for the treatment of mitochondrial disease, as well as the prevention of germline transmission of mutant mtDNA.
Glycosylation of dentin matrix protein 1 is a novel key element for astrocyte maturation and BBB integrity
Bo Jing, Chunxue Zhang, Xianjun Liu, Liqiang Zhou, Jiping Liu, Yinan Yao, Juehua Yu, Yuteng Weng, Min Pan, Jie Liu, Zuolin Wang, Yao Sun, Yi Eve Sun
2018, 9(3): 298-309. doi: 10.1007/s13238-017-0449-8
The blood-brain barrier (BBB) is a tight boundary formed between endothelial cells and astrocytes, which separates and protects brain from most pathogens as well as neural toxins in circulation. However, detailed molecular players involved in formation of BBB are not completely known. Dentin matrix protein 1 (DMP1)-proteoglycan (PG), which is known to be involved in mineralization of bones and dentin, is also expressed in soft tissues including brain with unknown functions. In the present study, we reported that DMP1-PG was expressed in brain astrocytes and enriched in BBB units. The only glycosylation site of DMP1 is serine89 (S89) in the N-terminal domain of the protein in mouse. Mutant mice with DMP1 point mutations changing S89 to glycine (S89G), which completely eradicated glycosylation of the protein, demonstrated severe BBB disruption. Another breed of DMP1 mutant mice, which lacked the C-terminal domain of DMP1, manifested normal BBB function. The polarity of S89G-DMP1 astrocytes was disrupted and cell-cell adhesion was loosened. Through a battery of analyses, we found that DMP1 glycosylation was critically required for astrocyte maturation both in vitro and in vivo. S89G-DMP1 mutant astrocytes failed to express aquaporin 4 and had reduced laminin and ZO1 expression, which resulted in disruption of BBB. Interestingly, overexpression of wild-type DMP1-PG in mouse brain driven by the nestin promoter elevated laminin and ZO1 expression beyond wild type levels and could effectively resisted intravenous mannitol-induced BBB reversible opening. Taken together, our study not only revealed a novel element, i.e., DMP1-PG, that regulated BBB formation, but also assigned a new function to DMP1-PG.
Zn(II) can mediate self-association of the extracellular C-terminal domain of CD147
Shujuan Jin, Pengfei Ding, Pengxiang Chu, Hongwei Li, Jianbo Sun, Dehai Liang, Fei Song, Bin Xia
2018, 9(3): 310-315. doi: 10.1007/s13238-017-0443-1