Advances in the Research on Induced Differentiation of Pluripotent Stem Cells into HematopoieticStem Progenitor Cells
Li Yanwei1*, Shan Wei2, Liu Li1, Huang Qiong1, Fang Sanhua1
1(Core Facilities, School of Medicine, Zhejiang University, Hangzhou 310058, China) 2(School of Basic Medical Sciences, Zhejiang University, Hangzhou 310058, China)
Abstract：Hematopoietic stem cells (HSC) transplantation is an effective means for the treatment of various hematological diseases. At present, allograft and autologous HSC transplantation are widely used in clinical practice, but there are still many problems, such as graft-versus-host disease caused by allogeneic transplantation, the limited number of HSC for autologous HSC transplantation. Pluripotent stem cells (PSC) including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the ability of self-renewal and multidirectional differentiation in vitro, which theoretically continuously produce HSC. However, there are still key scientific problems to be solved in the study of PSC hematopoietic differentiation, such as low efficiency in hematopoietic differentiation and difficulties to obtain PSC derived HSC that has long-term hematopoiesis potential in vivo. The reasons are that the internal regulation mechanism and external environment for PSC hematopoietic differentiation has not clear yet. This article reviewed the role of internal regulatory elements including transcription factors and signaling pathways, and external microenvironmental factors including stromal cells, cytokines and novel biomaterials in regulating PSC hematopoietic differentiation during in vitro and in vivo embryonic hematopoietic development, providing a theoretical basis for the study of PSC hematopoietic differentiation in vitro and clinical transformation of PSC-derived HSC.
李艳伟, 单威, 刘丽, 黄琼, 方三华. 多能干细胞向造血细胞定向诱导分化的研究进展[J]. 中国生物医学工程学报, 2023, 42(4): 502-512.
Li Yanwei, Shan Wei, Liu Li, Huang Qiong, Fang Sanhua. Advances in the Research on Induced Differentiation of Pluripotent Stem Cells into HematopoieticStem Progenitor Cells. Chinese Journal of Biomedical Engineering, 2023, 42(4): 502-512.
[1] Liu Senquan, Xu Yulin, Zhou Zijing, et al. Progress and challenges in generating functional hematopoietic stem/progenitor cells from human pluripotent stem cells[J]. Cytotherapy, 2015, 17(4):344-358. [2] Demirci S, Leonard A, Tisdale JF. Hematopoietic stem cells from pluripotent stem cells: clinical potential, challenges, and future perspectives [J]. Stem Cells Translational Medicine, 2020, 9(12): 1549-1557. [3] Wilkinson AC, Ishida R, Kikuchi M, et al. Long-term ex vivo haematopoietic-stem-cell expansion allows nonconditioned transplantation[J]. Nature, 2019, 571(7763):117-121. [4] Chou Binkuan, Ye Zaohui, Cheng Linzhao. Generation and homing of iPSC-derived hematopoietic cells in vivo[J]. Molecular Therapy: the Journal of the American Society of Gene Therapy, 2013, 21(7): 1292-1293. [5] Luo Qian, Li Honghu, Shan Wei, et al. Specific blood cells derived from pluripotent stem cells: an emerging field with great potential in clinical cell therapy [J]. Stem Cells International, 2021, 2021(4): 9919422. [6] Thambyrajah R, Bigas A. Notch signaling in HSC emergence: when, why and how[J]. Cells, 2022, 11(3): 358. [7] Gentek R, Ghigo C, Hoeffel G, et al. Hemogenic Endothelial Fate Mapping Reveals Dual Developmental Origin of Mast Cells[J]. Immunity, 2018, 48(6): 1160-1171. [8] Slukvin II. Hematopoietic specification from human pluripotent stem cells: current advances and challenges toward de novo generation of hematopoietic stem cells[J]. Blood, 2013, 122(25): 4035-4046. [9] Medvinsky A, Rybtsov S, Taoudi S. Embryonic origin of the adult hematopoietic system: advances and questions[J]. Development (Cambridge, England), 2011, 138(6): 1017-1031. [10] Helgason CD, Sauvageau G, Lawrence HJ, et al. Overexpression of HOXB4 enhances the hematopoietic potential of embryonic stem cells differentiated in vitro[J]. Blood, 1996, 87(7): 2740-2749. [11] Zeng Jiahui, Sun Wencui, Chang Jing, et al. HOXC4 up-regulates NF-κB signaling and promotes the cell proliferation to drive development of human hematopoiesis, especially CD43+ cells[J]. Blood Science (Baltimore, Md), 2020, 2(4): 117-128. [12] Izawa K, Yamazaki S, Becker HJ, et al. Activated HoxB4-induced hematopoietic stem cells from murine pluripotent stem cells via long-term programming [J]. Experimental Hematology, 2020, 89:68-79.e7. [13] Teichweyde N, Kasperidus L, Carotta S, et al. HOXB4 promotes hemogenic endothelium formation without perturbing endothelial cell development[J]. Stem Cell Reports, 2018, 10(3): 875-889. [14] Tashiro K, Kawabata K, Omori M, et al. Promotion of hematopoietic differentiation from mouse induced pluripotent stem cells by transient HoxB4 transduction[J]. Stem Cell Research, 2012, 8(2): 300-311. [15] Lengerke C, McKinney-Freeman S, Naveiras O, et al. The cdx-hox pathway in hematopoietic stem cell formation from embryonic stem cells[J]. Annals of the New York Academy of Sciences, 2007, 1106: 197-208. [16] Ramos-Mejía V, Navarro-Montero O, Ayllón V, et al. HOXA9 promotes hematopoietic commitment of human embryonic stem cells[J]. Blood, 2014, 124(20): 3065-3075. [17] Ran Dan, Shia Weijong, Lo Miaochia, et al. RUNX1a enhances hematopoietic lineage commitment from human embryonic stem cells and inducible pluripotent stem cells[J]. Blood, 2013, 121(15): 2882-2890. [18] Lange L, Morgan M, Schambach A. The hemogenic endothelium: a critical source for the generation of PSC-derived hematopoietic stem and progenitor cells[J]. Cellular and Molecular Life Sciences, 2021, 78(9): 4143-4160. [19] Hirai H, Samokhvalov IM, Fujimoto T, et al. Involvement of Runx1 in the down-regulation of fetal liver kinase-1 expression during transition of endothelial cells to hematopoietic cells[J]. Blood, 2005, 106(6): 1948-1955. [20] Ran Dan, Lam K, Shia Weijong, et al. Response: the role of RUNX1 isoforms in hematopoietic commitment of human pluripotent stem cells[J]. Blood, 2013, 121(26): 5252-5253. [21] Kitajima K, Minehata K, Sakimura K, et al. In vitro generation of HSC-like cells from murine ESCs/iPSCs by enforced expression of LIM-homeobox transcription factor Lhx2[J]. Blood, 2011, 117(14): 3748-3758. [22] D’Souza SL, Elefanty AG, Keller G. SCL/Tal-1 is essential for hematopoietic commitment of the hemangioblast but not for its development[J]. Blood, 2005, 105(10): 3862-3870. [23] Real PJ, Ligero G, Ayllon V, et al. SCL/TAL1 regulates hematopoietic specification from human embryonic stem cells [J]. Molecular Therapy: the Journal of the American Society of Gene Therapy, 2012, 20(7): 1443-1453. [24] Bruveris FF, Ng ES, Leitoguinho AR, et al. Human yolk sac-like haematopoiesis generates RUNX1-, GFI1- and/or GFI1B- dependent blood and SOX17-positive endothelium[J]. Development, 2020, 147(20): 101416-101431. [25] Clarke RL, Robitaille AM, Moon RT, et al. A quantitative proteomic analysis of hemogenic endothelium reveals differential regulation of hematopoiesis by SOX17[J]. Stem Cell Reports, 2015, 5(2): 291-304. [26] Wang Yu, Wang Hongtao, Guo Jiaojiao, et al. LGR4, not LGR5, enhances hPSC hematopoiesis by facilitating mesoderm induction via TGF-beta signaling activation[J]. Cell Reports, 2020, 31(5): 107600. [27] Tashiro K, Omori M, Kawabata K, et al. Inhibition of Lnk in mouse induced pluripotent stem cells promotes hematopoietic cell generation [J]. Stem Cells and Development, 2012, 21(18): 3381-3390. [28] Lis R, Karrasch CC, Poulos MG, et al. Conversion of adult endothelium to immunocompetent haematopoietic stem cells [J]. Nature, 2017, 545(7655):439-445. [29] Fidanza A, Forrester LM. Progress in the production of haematopoietic stem and progenitor cells from human pluripotent stem cells[J]. Journal of Immunology and Regenerative Medicine, 2021, 13: 100050. [30] Lomelí H, Castillo-Castellanos F. Notch signaling and the emergence of hematopoietic stem cells [J]. Developmental Dynamics, 2020, 249(11): 1302-1317. [31] Dietrich B, Haider S, Meinhardt G, et al. WNT and NOTCH signaling in human trophoblast development and differentiation[J]. Cellular and Molecular Life Sciences, 2022, 79(6): 292. [32] Jang Ilho, Lu Yifen, Zhao Long, et al. Notch1 acts via Foxc2 to promote definitive hematopoiesis via effects on hemogenic endothelium[J]. Blood, 2015, 125(9): 1418-1426. [33] Russo L, Sladitschek HL, Neveu PA. Multi-layered regulation of neuroectoderm differentiation by retinoic acid in a primitive streak-like context[J]. Stem Cell Reports, 2022, 17(2): 231-244. [34] Wu Yinyu, Hirschi KK. Regulation of hemogenic endothelial cell development and function [J]. Annual Review of Physiology, 2021, 83: 17-37. [35] Vijayaragavan K, Szabo E, Bossé M, et al. Noncanonical Wnt signaling orchestrates early developmental events toward hematopoietic cell fate from human embryonic stem cells[J]. Cell Stem Cell, 2009, 4(3):248-262. [36] Sturgeon CM, Ditadi A, Awong G, et al. Wnt signaling controls the specification of definitive and primitive hematopoiesis from human pluripotent stem cells[J]. Nature Biotechnology, 2014, 32(6): 554-561. [37] Wang Yi, Umeda K, Nakayama N. Collaboration between WNT and BMP signaling promotes hemoangiogenic cell development from human fibroblast-derived iPS cells[J]. Stem Cell Research, 2010, 4(3):223-231. [38] Wang Chengyan, Tang Xuming, Sun Xiaomeng, et al. TGFβ inhibition enhances the generation of hematopoietic progenitors from human ES cell-derived hemogenic endothelial cells using a stepwise strategy[J]. Cell Research, 2012, 22(1): 194-207. [39] Bai Hao, Xie Yinliang, Gao Yongxing, et al. The balance of positive and negative effects of TGF-β signaling regulates the development of hematopoietic and endothelial progenitors in human pluripotent stem cells[J]. Stem Cells and Development, 2013, 22(20): 2765-2776. [40] Saxena S, Rönn RE, Guibentif C, et al. Cyclic AMP signaling through epac axis modulates human hemogenic endothelium and enhances hematopoietic cell generation[J]. Stem Cell Reports, 2016, 6(5):692-703. [41] Kaufman DS, Hanson ET, Lewis RL, et al. Hematopoietic colony-forming cells derived from human embryonic stem cells[J]. Proceedings of the National Academy of Sciences of the United States of America, 2001, 98(19): 10716-10721. [42] Demirci S, Haro-Mora JJ, Leonard A, et al. Definitive hematopoietic stem/progenitor cells from human embryonic stem cells through serum/feeder-free organoid-induced differentiation[J]. Stem Cell Research & Therapy, 2020, 11(1): 493. [43] Qiu Caihong, Hanson E, Olivier E, et al. Differentiation of human embryonic stem cells into hematopoietic cells by coculture with human fetal liver cells recapitulates the globin switch that occurs early in development[J]. Experimental Hematology, 2005, 33(12): 1450-1458. [44] Ledran MH, Krassowska A, Armstrong L, et al. Efficient hematopoietic differentiation of human embryonic stem cells on stromal cells derived from hematopoietic niches[J]. Cell Stem Cell, 2008, 3(1): 85-98. [45] Gordon-Keylock SAM, Jackson M, Huang CX, et al. Induction of hematopoietic differentiation of mouse embryonic stem cells by an AGM-derived stromal cell line is not further enhanced by overexpression of HOXB4[J]. Stem Cells and Development, 2010, 19(11): 1687-1698. [46] Shan Wei, Yu Qin, Long Yan, et al. Enhanced HSC-like cell generation from mouse pluripotent stem cells in a 3D induction system cocultured with stromal cells [J]. Stem Cell Research & Therapy, 2021, 12(1): 353. [47] Chen Xiaoli, Zhao Qianhao, Li Chen, et al. OP9-Lhx2 stromal cells facilitate derivation of hematopoietic progenitors both in vitro and in vivo[J]. Stem Cell Research, 2015, 15(2): 395-402. [48] Yang Chao, Ji Lei, Yue Wen, et al. Human fetal liver stromal cells expressing erythropoietin promote hematopoietic development from human embryonic stem cells[J]. Cellular Reprogramming, 2012, 14(1): 88-97. [49] Gori JL, Butler JM, Chan Yanyi, et al. Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells[J]. The Journal of Clinical Investigation, 2015, 125(3): 1243-1254. [50] Sugimura R, Jha DK, Han A, et al. Haematopoietic stem and progenitor cells from human pluripotent stem cells[J]. Nature, 2017, 545(7655):432-438. [51] Chadwick K, Wang Lisheng, Li Li, et al. Cytokines and BMP-4 promote hematopoietic differentiation of human embryonic stem cells[J]. Blood, 2003, 102(3): 906-915. [52] Pearson S, Sroczynska P, Lacaud G, et al. The stepwise specification of embryonic stem cells to hematopoietic fate is driven by sequential exposure to Bmp4, activin A, bFGF and VEGF[J]. Development (Cambridge, England), 2008, 135(8): 1525-1535. [53] Nasrallah R, Knezevic K, Thai T, et al. Endoglin potentiates nitric oxide synthesis to enhance definitive hematopoiesis[J]. Biology Open, 2015, 4(7): 819-829. [54] Yu QC, Hirst CE, Costa M, et al. APELIN promotes hematopoiesis from human embryonic stem cells[J]. Blood, 2012, 119(26): 6243-6254. [55] Cerdan C, McIntyre BAS, Mechael R, et al. Activin A promotes hematopoietic fated mesoderm development through upregulation of brachyury in human embryonic stem cells[J]. Stem Cells and Development, 2012, 21(15): 2866-2877. [56] Gertow K, Hirst CE, Yu QC, et al. WNT3A promotes hematopoietic or mesenchymal differentiation from hESCs depending on the time of exposure[J]. Stem Cell Reports, 2013, 1(1):53-65. [57] Hirota S, Ogawa M. Activin A in combination with OP9 cells facilitates development of Flk-1+ PDGFRα－ and Flk-1+ PDGFRα+ hematopoietic mesodermal cells from murine embryonic stem cells[J]. Biochemical and Biophysical Research Communications, 2015, 467(3): 583-588. [58] Pearson S, Cuvertino S, Fleury M, et al. In vivo repopulating activity emerges at the onset of hematopoietic specification during embryonic stem cell differentiation[J]. Stem Cell Reports, 2015, 4(3): 431-444. [59] Wang Yv, Gao Jie, Wang Hongtao, et al. R-spondin2 promotes hematopoietic differentiation of human pluripotent stem cells by activating TGF beta signaling[J]. Stem Cell Research & Therapy, 2019, 10(1): 136. [60] Atkins MH, Scarfò R, McGrath KE, et al. Modeling human yolk sac hematopoiesis with pluripotent stem cells [J]. The Journal of Experimental Medicine, 2022, 219(3): e20211924. [61] Oguro H. Generation of hematopoietic stem and progenitor cells from human pluripotent stem cells[J]. Methods in Molecular Biology, 2019, 2048: 245-257. [62] Zhang Sophia, Dutton JR, Su Liping, et al. The influence of a spatiotemporal 3D environment on endothelial cell differentiation of human induced pluripotent stem cells[J]. Biomaterials, 2014, 35(12): 3786-3793. [63] Xu Mengxue, Liu Liping, Li Yumei, et al. The opportunities and challenges regarding induced platelets from human pluripotent stem cells[J]. Stem Cells International, 2021, 2021(2): 5588165. [64] Shan Wei, Wang Binsheng, Xu Yulin, et al. Generation of hematopoietic cells from mouse pluripotent stem cells in a 3D culture system of self-assembling peptide hydrogel[J]. Journal of Cellular Physiology, 2020, 235(3): 2080-2090. [65] Xu Yulin, Shan Wei, Li Xia, et al. A synthetic three-dimensional niche system facilitates generation of functional hematopoietic cells from human-induced pluripotent stem cells[J]. Journal of Hematology & Oncology, 2016, 9(1):102. [66] Przybyla L, Lakins JN, Weaver VM. Tissue mechanics orchestrate wnt-dependent human embryonic stem cell differentiation[J]. Cell Stem Cell, 2016, 19(4):462-475. [67] Doulatov S, Vo LT, Chou SS, et al. Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via respecification of lineage-restricted precursors[J]. Cell Stem Cell, 2013, 13(4):459-470. [68] Lee J, Dykstra B, Sackstein R, et al. Progress and obstacles towards generating hematopoietic stem cells from pluripotent stem cells [J]. Current Opinion in Hematology, 2015, 22(4): 317-323. [69] Tan Yuting, Ye Lin, Xie Fei, et al. Respecifying human iPSC-derived blood cells into highly engraftable hematopoietic stem and progenitor cells with a single factor[J]. Proceedings of the National Academy of Sciences of the United States of America, 2018, 115(9): 2180-2185. [70] Martin RM, Fowler JL, Cromer MK, et al. Improving the safety of human pluripotent stem cell therapies using genome-edited orthogonal safeguards [J]. Nature Communications, 2020, 11(1): 2713. [71] Kaufman DS. Toward clinical therapies using hematopoietic cells derived from human pluripotent stem cells [J]. Blood, 2009, 114(17): 3513-3523. [72] Anurogo D, Yuli Prasetyo Budi N, Thi Ngo MH, et al. Cell and gene therapy for Anemia: hematopoietic stem cells and gene editing[J]. International Journal of Molecular Sciences, 2021, 22(12): 6275. [73] Gandre-Babbe S, Paluru P, Aribeana C, et al. Patient-derived induced pluripotent stem cells recapitulate hematopoietic abnormalities of juvenile myelomonocytic leukemia [J]. Blood, 2013, 121(24):4925-4929.
