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人才隊伍

李勁松
研究員，中科院院士，博士生導師，細胞生物學國家重點實驗室主任
E-mail: jsli@@sibcb.ac.cn
實驗室主頁:

個人簡介：

　　1993年7月畢業(yè)于江西農(nóng)業(yè)大學畜牧獸醫(yī)系，獲理學學士學位；1996年7月畢業(yè)于揚州大學畜牧獸醫(yī)學院，獲理學碩士學位；2002年7月畢業(yè)于中國科學院動物研究所，獲理學博士學位;2002年8月至2007年7月在美國洛克菲勒大學從事博士后研究；2007年8月起任中科院上海生科院生物化學與細胞生物學研究所研究員，研究組長。2012年獲“杰出青年基金”支持。

社會任職：

研究方向：

干細胞與胚胎發(fā)育

研究工作：

　　生殖細胞不能在體外培養(yǎng)和增殖，極大地限制了生殖發(fā)育生物學發(fā)展。2012年，實驗室利用核移植和干細胞技術(shù)，成功地建立了可無限增殖的小鼠孤雄單倍體胚胎干細胞系(又稱為類精子干細胞)，并證明其可功能性地代替精子繁育健康小鼠，創(chuàng)建了半克隆技術(shù);2015年，我們發(fā)現(xiàn)H19-DMR和IG-DMR雄性印記基因表達調(diào)控區(qū)域是半克隆胚胎發(fā)育的主要障礙，通過敲除這兩個區(qū)域使健康半克隆小鼠出生率提高了10倍;實驗室還建立了人的類精子干細胞及食蟹猴和人孤雌單倍體胚胎干細胞。這些系統(tǒng)性研究成果產(chǎn)生了集單倍體性、自我更新、多能性和“受精”能力為一體的新型干細胞，為揭示有性繁殖的奧秘、深入進行生殖發(fā)育的轉(zhuǎn)化研究和造福人類生殖健康的重要工具。
　　基因編輯是研究其功能的主要手段，然而，哺乳動物的精準復雜遺傳改造仍然困難重重。類精子干細胞突破了精子不能被遺傳編輯的瓶頸，可攜帶不同的基因修飾或基因編輯器，并通過“授精”傳遞到小鼠胚胎中，為精準和復雜基因編輯小鼠的構(gòu)建及在體遺傳篩選奠定了基礎。2015年以來，我們利用用該技術(shù)體系，圍繞發(fā)育生殖、疾病模擬、染色體工程等開展應用研究，取得了一系列成果，拓展了哺乳動物遺傳改造研究的領(lǐng)域，包括：
　　1. 結(jié)合類精子干細胞與單堿基編輯系統(tǒng)，實現(xiàn)了原始生殖細胞發(fā)育必需蛋白質(zhì)DND1關(guān)鍵氨基酸的靶向突變篩選，建立了在體關(guān)鍵氨基酸的遺傳篩選方法。
　　2. 結(jié)合類精子干細胞和CRISPR-Cas9基因編輯文庫，實現(xiàn)了骨骼發(fā)育關(guān)鍵基因的靶向遺傳篩選。
　　3. 在類精子干細胞中敲除多個基因，通過“授精”一步獲得了多基因雜合敲除小鼠，模擬了人類復雜疾病Ⅰ型強直性肌營養(yǎng)不良癥(DM1)的大部分病癥，證實多基因劑量不足是DM1關(guān)鍵病因，為快速構(gòu)建復雜疾病小鼠模型提供了新策略。
　　4. 在類精子干細胞上開展染色體改造，獲得多個攜帶19對染色體的小鼠模型，模擬了自然界中最常見的染色體演化事件，為在哺乳動物中開展染色體改造研究奠定了基礎。
　　5. 全基因組蛋白質(zhì)標簽小鼠資源庫將極大地促進生命科學研究，但傳統(tǒng)方法難以實現(xiàn)該資源庫構(gòu) 建。我們啟動了基因組標簽計劃(genome tagging project, GTP)，利用類精子干細胞進行基因原位打靶，建立全蛋白質(zhì)組標簽細胞系，通過“授精”可獲得蛋白質(zhì)的標簽小鼠，有望為促進生物醫(yī)學研究提供有價值的資源。
　　目前，實驗室圍繞單倍體胚胎干細胞及半克隆技術(shù)開展四方面研究：
　　1. 單倍體胚胎干細胞自身帶來的問題，如自發(fā)二倍體化的機制等;
　　2. 類精子干細胞作為精子替代物的問題，如，如何進一步提高半克隆胚胎的發(fā)育潛力等;
　　3. 半克隆技術(shù)在構(gòu)建復雜遺傳改造小鼠模型中的應用;
　　4. 生殖細胞發(fā)育的調(diào)控網(wǎng)絡研究。

承擔科研項目情況：

代表論著：

（#Co-first authors, *: Correspondence authors）
- 一、類精子干細胞介導半克隆技術(shù)相關(guān)論文（2012年—至今）
1. Zhang XM^#, Yan M^#, Yang Z^#, Xiang H^#, Tang W, Cai X, Wu Q, Liu X, Pei G & Li J*. Creation of artificial karyotypes in mice reveals robustness of genome organization. Cell Res 32(11)(2022), 1026–1029.
2. Zhang H^#, Li Y^#, Ma Y^#, Lai C, Yu Q, Shi G, Li J*. Epigenetic integrity of paternal imprints enhances the developmental potential of androgenetic haploid embryonic stem cells. Protein & Cell 13(2)(2021), 102-119.
3. Zhang XM^#, Wu K^#, Zheng Y^#, Zhao H^#, Gao J, Hou Z, Zhang M, Liao J, Zhang J, Gao Y, Li Y, Li L, Tang F*, Chen ZJ* & Li J*. In vitro expansion of human sperm through nuclear transfer. Cell Research 30(4)(2020), 356-359.
4. Yin Q^#, Wang H^#, Li N^#, Ding Y^#, Xie Z^#, Jin, L^#, Li Y, Wang Q, Liu X, Xu L, Li Q, Ma Y, Cheng Y, Wang K, Zhong C, Yu Q, Tang W, Chen W, Yang W, Zhang F, Ding C, Bao L, Zhou B, Hu P* & Li J*. Dosage effect of multiple genes accounts for multisystem disorder of myotonic dystrophy type 1. Cell Research 30(2)(2020), 133-145. Cover story
5. Li Q^#, Li Y^#, Yin Q^#, Huang S^#, Wang K^#, Zhuo L, Li W, Chang B & Li J*. Temporal regulation of prenatal embryonic development by paternal imprinted loci. Sci China Life Sci 63(1)(2020), 1-17. Cover story
6. Wang L^#, Zhang Y^#, Fu X^#, Dong S^#, Tang S, Zhang N, Song C, Yang N, Zhang L, Wang H, Shi H, Jin L, Zhang F*, Li J* & Hua K*. Joint utilization of genetic analysis and semi-cloning technology reveals a digenic etiology of Mu？llerian anomalies. Cell Res 30(1)(2020), 91-94.
7. Bai M^#, Han Y^#, Wu Y, Liao J, Li L, Wang L, Li Q, Xing w, Chen L, Zou W* & Li J*. Targeted genetic screening in mice through haploid embryonic stem cells identifies critical genes in bone development. PLOS Biology 17(7)(2019), e3000350.
8. Jiang J, Yan M, Li D & Li J*. Genome tagging project: tag every protein in mouse through “artificial spermatids”. Nat Sci Rev 6(3)(2019), 394-396.
9. Li Q^#, Li Y^#, Yang S, Huang S, Yan M, Ding Y, Tang W, Lou X, Yin Q, Sun Z, Lu L, Shi H, Wang H, Chen Y* & Li J*. CRISPR-Cas9-mediated base-editing screening in mice identifies DND1 amino acids that are critical for primordial germ cell development. Nat Cell Biol 20(11)(2018), 1315-1325.
10. Qu C, Yan M, Yang S, Wang L, Yin Q, Liu Y, Chen Y & Li J*. Haploid embryonic stem cells can be enriched and maintained by simple filtration. J Biol Chem 293 (14) (2018), 5230-5235.
11. Wei L, Wang X, Yang S, Yuan W* & Li J*. Efficient generation of the mouse model with a defined point mutation through haploid cell-mediated gene-editing. J Genet Genomics 44(9)(2017), 461-463.
12. Xu H, Yue C, Zhang T, Li Y, Guo A, Liao J, Pei G, Li J* & Jing N*. Derivation of haploid neurons from mouse androgenetic haploid embryonic stem cells. Neurosci Bull 33(3)(2017), 361-364.
13. Zhong C ^#, Zhang M^#, Yin Q, Zhao H, Wang Y, Huang S, Tao W, Wu K*, Chen Z-J* & Li J*. Generation of human haploid embryonic stem cells from parthenogenetic embryos obtained by microsurgical removal of male pronucleus. Cell Res 26(6)(2016), 743-746.
14. Zhong C ^#, Xie Z^#, Yin Q^#, Dong R, Yang S, Wu Y & Li J*. Parthenogenetic haploid embryonic stem cells efficiently support mouse generation by oocyte injection. Cell Res 26(1)(2016), 131-134.
15. Zhong C ^#, Yin Q^#, Xie Z^#, Bai M^#, Dong R^#, Tang W, Xing Y, Zhang H, Yang S, Chen L-L, Bartolomei MS, Ferguson-Smith A, Li D, Yang L*, Wu Y* & Li J*. CRISPR-Cas9-mediated genetic screening in mice with haploid embryonic stem cells carrying a guide RNA library. Cell Stem Cell 17(2)(2015), 221-232.
16. Yang H^#, Liu Z^#, Ma Y^#, Zhong C, Yin Q, Zhou C, Shi L, Cai Y, Zhao H, Wang H, Tang F, Wang Y, Zhang C, Liu X, Lai D, Jin Y*, Sun Q* & Li J*. Generation of haploid embryonic stem cells from Macaca fascicularis monkey parthenotes. Cell Res 23(10)(2013), 1187-1200.
17. Yang H^#, Shi L^#, Wang B^#, Liang D, Zhong C, Liu W, Nie Y, Liu J, Zhao J, Gao X, Li D, Xu G-L* & Li J*. Generation of genetically modified mice by oocyte injection of androgenetic haploid embryonic stem cells. Cell 149(3)(2012), 605-617.
  - 二、生殖細胞發(fā)育、基因編輯及治療相關(guān)論文（2013年—至今）
18. Li Q^#, Lu J^#, Yin X^#, Chang Y^#, Wang C^#, Yan M^#, Feng L, Cheng Y, Gao Y, Xu B, Zhang Y, Wang Y, Cui G, Xu L, Sun Y, Zeng R, Li Y, Jing N, Xu GL*, Wu L*, Tang F* & Li J*. Base editing-mediated one-step inactivation of the Dnmt gene family reveals critical roles of DNA methylation during mouse gastrulation. Nat Commun 14(1)(2023): 2922.
19. Fu J^#, Li Q^#, Liu X^#, Tu T^#, Lv X, Yin X, Lv J, Song Z, Qu J, Zhang J, Li J* & Gu F*. Human cell based directed evolution of adenine base editors with improved efficiency. Nat Commun 12(1)(2021), 5897.
20. Zhao T^#, Li Q^#, Zhou C^#, Lv X^#, Liu H, Tu T, Tang N, Cheng Y, Liu X, Liu C, Zhao J, Song Z, Wang H, Li J* & Gu F*. Small-molecule compounds boost genome-editing efficiency of cytosine base editor. Nucleic Acids Res 49(15)(2021), 8974-8986.
21. Li S^#, Li X^#, Xue W^#, Zhang L^#, Yang LZ, Cao SM, Lei YN, Liu CX, Guo SK, Shan L, Wu M, Tao X, Zhang JL, Gao X, Zhang J, Wei J, Li J*, Yang L* & Chen L*. Screening for functional circular RNAs using the CRISPR–Cas13 system. Nat Methods 18(1)(2021), 51-59.
22. Wang Y*, Yan M*, Zhang X*, Liu X, Lai C, Ding Y, Tong MH* & Li J*. Rescue of male infertility through correcting a genetic mutation causing meiotic arrest in spermatogonial stem cells. Asian J Andrology 23(6)2021, 590-599.
23. Wang X^#, Kang JY^#, Wei L^#, Yang X^#, Sun H, Yang S, Liu L, Yan M, Bai M, Chen Y, Long J, Li N, Li D, Huang J, Lei M, Shao Z, Yuan W*, Zuo E*, Lu K*, Liu MF* & Li J*. PHF7 is a novel histone H2A E3 ligase prior to histone-to-protamine exchange during spermiogenesis. Development 146(13)(2019), dev175547.
24. Chen Y, Zheng Y, Gao Y, Lin Z, Yang S, Wang T, Wang Q, Xie N, Hua R, Liu M, Sha J, Griswold MD, Li J*, Tang F* & Tong M*. Single-cell RNA-seq uncovers dynamic processes and critical regulators in mouse spermatogenesis. Cell Res 28(9)(2018), 879-896.
25. Wang L^#, Li MY^#, Qu C, Miao WY, Yin Q, Liao J, Cao HT, Huang M, Wang K, Zuo E, Peng G, Zhang SX, Chen G, Li Q, Tang K, Yu Q, Li Z, Wong C, Xu G, Jing N, Yu X* & Li J*. CRISPR-Cas9-mediated genome-editing in one blastomere of two-cell embryos reveals a novel Tet3 function in regulating neocortical development. Cell Res 27(6)(2017), 815-829.
26. Wu K^#, Zhong C^#, Chen T^#, Zhang X, Tao W, Zhang J, Li H, Zhao H*, Li J* & Chen ZJ*. Polar bodies are efficient donors for reconstruction of human embryos for potential mitochondrial replacement therapy. Cell Res 27(8)(2017), 1069-1072.
27. Bai M, Liang D, Wang Y, Li Q, Wu Y & Li J*. Spermatogenic cell-specific gene mutation in mice via CRISPR-Cas9. J Genet Genomics 43(5)(2016), 289-296.
28. Wu Y^#, Zhou H^#, Fan X^#, Zhang Y^#, Zhang M^#, Wang Y, Xie Z, Bai M, Yin Q, Liang D, Tang W, Liao J, Zhou C, Liu W, Zhu P, Guo H, Pan H, Wu C, Shi H, Wu L*, Tang F* & Li J*. Correction of a genetic disease by CRISPR-Cas9-mediated gene editing in mouse spermatogonial stem cells. Cell Res 25(1)(2015), 67-79.
29. Zhang M, Zhou H, Zheng C, Xiao J, Zuo E, Liu W, Xie D, Shi Y, Wu C, Wang H, Li D & Li J*. The roles of testicular c-kit positive cells in de novo morphogenesis of testis. Sci Rep 4(2014), 5936. doi: 10.1038/srep05936.
30. Wu Y^#, Liang D^#, Wang Y, Bai M, Tang W, Bao S, Yan Z, Li D & Li J*. Correction of a genetic disease in mouse via use of CRISPR-Cas9. Cell Stem Cell 13(6)(2013), 659-662.
  - 三、細胞重編程相關(guān)論文（2007年—2013年）
31. Qin Y^#, Lin J^#, Zhou C^#, Yin Q, Xie Z, Zhang X, Liu X, Gao W & Li J*. Mice cloned from white adipose tissue-derived cells. J Mol Cell Biol 5(5)(2013), 348-350.
32. Guo F^#, Li X^#, Liang D^#, Li T^#, Zhu P, Guo H, Wu X, Wen L, Gu T, Hu B, Walsh CP, Li J*, Tang F* & Xu G*. Active and passive demethylation of male and female pronuclear DNA in the mammalian zygote. Cell Stem Cell 15(4)(2014), 447-458.
33. Jiang J^#, Lv W^#, Ye X, Wang L, Zhang M, Yang H, Okuka M, Zhou C, Zhang X, Liu L* & Li J*. Zscan4 promotes genomic stability during reprogramming and dramatically improves the quality of iPS cells as demonstrated by tetraploid complementation. Cell Res 23(1)(2013), 92-106.
34. Jiang J^#, Ding G^#, Lin J^#, Zhang M, Shi L, Lv W, Yang H, Xiao H, Pei G, Li Y, Wu J* & Li J*. Different developmental potential of pluripotent stem cells generated by different reprogramming strategies. J Mol Cell Biol 3(3)(2011), 197-199.
35. Gu T^#, Guo F^#, Yang H^#, Wu HP, Xu GF, Liu W, Xie ZG, Shi L, He X, Jin SG, Iqbal K, Shi YG, Deng Z, Szabo PE, Pfeifer GP, Li J* & Xu GL*. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 477(7366)(2011), 606-610.
36. Lin J, Shi L, Zhang M, Yang H, Qin Y, Zhang J, Gong D, Zhang X, Li D & Li J*. Defects in trophoblast cell lineage account for the impaired in vivo development of cloned embryos generated by somatic nuclear transfer. Cell Stem Cell 8(4)(2011), 371-375.
  - 四、應邀綜述、評論（2012年—至今）
37. Li J* & Zeng Y*. Preface to the special topic on tissue stem cell research. Science China Life Science 62(6)(2021), 865-867. (Editoral)
38. Yan M & Li J*. Combined application of CRISPR-Cas9 and stem Cells for clinical and basic research. Cell Regeneration 9(2020), 19.
39. Yan M & Li J*. The evolving CRISPR technology. Protein Cell 10(11)(2019), 783-786.
40. Wang L & Li J*. Expansion of mutant monkey through cloning. Science China Life Science 62(6)(2019), 865-867. (Highlight)
41. Li Y & Li J*. Technical advances contribute to the study of genome imprinting. PLOS Genet 15(6)(2019), e1008151. (Invited review)
42. Wang L & Li J*. ‘Artificial spermatid’-mediated genome editing. Biol Reprod 101(3)(2019), 538-548. (Invited review)
43. Li J* & Gao C*. Preface to the special topic on genome editing research in China. Nat Sci Rev 6(3)(2019), 389-390.
44. Wang X & Li J*. An intermediate cell state allows rerouting of cell fate. J Biol Chem 292(46)(2017), 19133-19134. (Highlight).
45. Wang Y, Ding Y & Li J*. CRISPR-Cas9-mediated gene editing in mouse spermatogonial stem cells. Methods Mol Biol 1622(2017), 293-305.
46. Zhong C & Li J*. Efficient generation of gene-modified mice by haploid embryonic stem cell-mediated semi-cloned technology. Methods Mol Biol 1498 (2017), 121-133.
47. Bai M, Wu Y & Li J*. Generation and application of mammalian haploid embryonic stem cells. J Intern Med 280(3)(2016), 236-245. (Invited Review)
48. Tong M* & Li J*. Similarity of epigenetic reprogramming in primordial germ cells between human and mouse. Natl Sci Rev 2(4)(2015), 384. (Invited Research Highlights)
49. Li J. Stem cell, basis and application. Sci Bull 60(20)(2015), 1711-1712.
50. Shi L, Yang H & Li J*. Haploid embryonic stem cells: an ideal tool for mammalian genetic analyses. Protein & Cell 3(11)(2012), 806-810. (Invited review)
  - 五、2007年以前的代表性論文
51. Li J & Mombaerts P. Nuclear transfer-mediated rescue of the nuclear genome of nonviable mouse cells frozen without cryoprotectant. Biol Reprod 79(4)(2008), 588-593.
52. Li J^#, Guasch G^#, Greco V^#, Fuchs E* & Mombaerts P*. Cloned mice from Skin Stem Cells. Proc Natl Acad Sci USA 104(8)(2007), 2738-2743.
53. Li J, Ishii T, Wen D & Mombaerts P. Non-equivalence of cloned and clonal mice. Curr Biol 15(18)(2005), R756-R757.
54. Li J, Ishii T, Feinstein P & Mombaerts P. Odorant receptor gene choice is reset by nuclear transfer from mouse olfactory sensory neurons. Nature 428(6981)(2004), 393-398.
55. Chen D^#, Li J^#, Han Z, Lei L, Liu Z, Kou Z, Ma S, Du Q & Sun Q. Somatic cell bovine cloning: efficiency of donor cells from female and male using different recipient cows. Chin Sci Bull 48(6)(2003), 549-554.

獲獎及榮譽：

研究組成員：

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