2022 Vol. 13, No. 11

Hematopoietic stem cell transplantation has been successfully employed in treating hematological diseases. However, approximately 5%–46% of donors fail to mobilize their HSPCs. Xu et al. developed a polypeptide-forming three-dimension culture system (3DCS) to efficiently expand rare HSPCs circulating in steady peripheral blood (cHSPCs). The 3DCS fabricated an immunomodulatory niche (the soil), secreting cytokines as TNF-α to support the survival and multi-lineage differentiation (apples on the tree) of cHSPCs (the seed) in patients/donors who have failed in HSPC mobilization.

Recollections
Tsai Chiao: The founder of physiology and aviation, aerospace and navigation medicine in China
Yalan Wang, Zijian Li, Yanyan Qian, Benyu Guo
2022, 13(11): 779-784. doi: 10.1007/s13238-020-00737-3
Abstract:
Qi Fang: Affective interweave with patients
Tanping Fu, Wenli Duan, Mingyan Chen, Shuyang Zhang
2022, 13(11): 785-789. doi: 10.1007/s13238-019-00667-9
Abstract:
Review
Connecting past and present: single-cell lineage tracing
Cheng Chen, Yuanxin Liao, Guangdun Peng
2022, 13(11): 790-807. doi: 10.1007/s13238-022-00913-7
Abstract:
Central to the core principle of cell theory, depicting cells’ history, state and fate is a fundamental goal in modern biology. By leveraging clonal analysis and single-cell RNA-seq technologies, single-cell lineage tracing provides new opportunities to interrogate both cell states and lineage histories. During the past few years, many strategies to achieve lineage tracing at single-cell resolution have been developed, and three of them (integration barcodes, polylox barcodes, and CRISPR barcodes) are noteworthy as they are amenable in experimentally tractable systems. Although the above strategies have been demonstrated in animal development and stem cell research, much care and effort are still required to implement these methods. Here we review the development of single-cell lineage tracing, major characteristics of the cell barcoding strategies, applications, as well as technical considerations and limitations, providing a guide to choose or improve the single-cell barcoding lineage tracing.
Research Articles
Efficient expansion of rare human circulating hematopoietic stem/progenitor cells in steady-state blood using a polypeptide-forming 3D culture
Yulin Xu, Xiangjun Zeng, Mingming Zhang, Binsheng Wang, Xin Guo, Wei Shan, Shuyang Cai, Qian Luo, Honghu Li, Xia Li, Xue Li, Hao Zhang, Limengmeng Wang, Yu Lin, Lizhen Liu, Yanwei Li, Meng Zhang, Xiaohong Yu, Pengxu Qian, He Huang
2022, 13(11): 808-824. doi: 10.1007/s13238-021-00900-4
Abstract:
Although widely applied in treating hematopoietic malignancies, transplantation of hematopoietic stem/progenitor cells (HSPCs) is impeded by HSPC shortage. Whether circulating HSPCs (cHSPCs) in steady-state blood could be used as an alternative source remains largely elusive. Here we develop a three-dimensional culture system (3DCS) including arginine, glycine, aspartate, and a series of factors. Fourteen-day culture of peripheral blood mononuclear cells (PBMNCs) in 3DCS led to 125- and 70-fold increase of the frequency and number of CD34+ cells. Further, 3DCS-expanded cHSPCs exhibited the similar reconstitution rate compared to CD34+ HSPCs in bone marrow. Mechanistically, 3DCS fabricated an immunomodulatory niche, secreting cytokines as TNF to support cHSPC survival and proliferation. Finally, 3DCS could also promote the expansion of cHSPCs in patients who failed in HSPC mobilization. Our 3DCS successfully expands rare cHSPCs, providing an alternative source for the HSPC therapy, particularly for the patients/donors who have failed in HSPC mobilization.
Genome-wide CRISPR screen identifies synthetic lethality between DOCK1 inhibition and metformin in liver cancer
Junru Feng, Hui Lu, Wenhao Ma, Wenjing Tian, Zhuan Lu, Hongying Yang, Yongping Cai, Pengfei Cai, Yuchen Sun, Zilong Zhou, Jiaqian Feng, Jiazhong Deng, Ying Shu, Kun Qu, Weidong Jia, Ping Gao, Huafeng Zhang
2022, 13(11): 825-841. doi: 10.1007/s13238-022-00906-6
Abstract:
Metformin is currently a strong candidate anti-tumor agent in multiple cancers. However, its anti-tumor effectiveness varies among different cancers or subpopulations, potentially due to tumor heterogeneity. It thus remains unclear which hepatocellular carcinoma (HCC) patient subpopulation(s) can benefit from metformin treatment. Here, through a genome-wide CRISPR-Cas9-based knockout screen, we find that DOCK1 levels determine the anti-tumor effects of metformin and that DOCK1 is a synthetic lethal target of metformin in HCC. Mechanistically, metformin promotes DOCK1 phosphorylation, which activates RAC1 to facilitate cell survival, leading to metformin resistance. The DOCK1-selective inhibitor, TBOPP, potentiates anti-tumor activity by metformin in vitro in liver cancer cell lines and patient-derived HCC organoids, and in vivo in xenografted liver cancer cells and immunocompetent mouse liver cancer models. Notably, metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 expression. This study shows that metformin effectiveness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for metformin-resistant HCC patients.
Postnatal state transition of cardiomyocyte as a primary step in heart maturation
Zheng Li, Fang Yao, Peng Yu, Dandan Li, Mingzhi Zhang, Lin Mao, Xiaomeng Shen, Zongna Ren, Li Wang, Bingying Zhou
2022, 13(11): 842-862. doi: 10.1007/s13238-022-00908-4
Abstract:
Postnatal heart maturation is the basis of normal cardiac function and provides critical insights into heart repair and regenerative medicine. While static snapshots of the maturing heart have provided much insight into its molecular signatures, few key events during postnatal cardiomyocyte maturation have been uncovered. Here, we report that cardiomyocytes (CMs) experience epigenetic and transcriptional decline of cardiac gene expression immediately after birth, leading to a transition state of CMs at postnatal day 7 (P7) that was essential for CM subtype specification during heart maturation. Large-scale single-cell analysis and genetic lineage tracing confirm the presence of transition state CMs at P7 bridging immature state and mature states. Silencing of key transcription factor JUN in P1-hearts significantly repressed CM transition, resulting in perturbed CM subtype proportions and reduced cardiac function in mature hearts. In addition, transplantation of P7-CMs into infarcted hearts exhibited cardiac repair potential superior to P1-CMs. Collectively, our data uncover CM state transition as a key event in postnatal heart maturation, which not only provides insights into molecular foundations of heart maturation, but also opens an avenue for manipulation of cardiomyocyte fate in disease and regenerative medicine.
Letter
Gonadal mosaicism mediated female-biased gender control in mice
Meizhu Bai, Dan Liang, Yan Cheng, Guolong Liu, Qiudao Wang, Jinsong Li, Yuxuan Wu
2022, 13(11): 863-868. doi: 10.1007/s13238-022-00910-w
Abstract: