隨著人類平均壽命延長，高齡群體對醫療服務的需求增加，導致血液的需求逐年增加。然而，在世界衛生組織2015 ~ 2018年的調查，全世界每年捐血約1.2億單位，其中42%來自高收入國家，但全球僅有16 %的人口生活在這些國家，並且，隨著人口老化和出生率降低使得捐血者人數逐年減少。因此，開發出穩定且高品質的輸血來源成為紓解血液短缺問題的解方。
近年來有許多研究透過誘導多功能幹細胞、胚胎幹細胞等技術增殖紅血球，但仍受擴增率低與血紅蛋白濃度不足所限，因此有許多研究致力開發使用細胞激素或小分子藥物之紅血球分化培養基，尤其小分子藥物具有穿過細胞膜、不具有免疫原性、低成本且易於控制變量等優點。
本實驗大致可分為兩階段，第一階段：基於先前實驗開發出無血清造血幹細胞培養基，配合四種小分子藥物：UM729、SR1、5α-THB與5β-THB，配合無血清培養基培養7天後，以細胞增殖的倍數、細胞的表面標誌物與群落形成實驗等分析其功能性與有效性，篩選出適合造血幹細胞增殖之濃度。第二階段：基於實驗室開發之無血清紅血球分化培養基，配合篩選出之濃度，分化培養7天後，以細胞增殖的倍數、細胞的表面標誌物、細胞型態與血紅蛋白分析等實驗分析為基準，建立出培養出紅血球前驅細胞的培養方法。
實驗結果證明，添加UM729與SR1能擴增造血幹細胞達15倍，且流式細胞儀結果證明，能使CD34+及CD38-比例分別維持78%與48%，為控制組的2.9倍與1.8倍，但其對紅血球分化並沒有正面的影響。添加5α-THB與5β-THB則對造血幹細胞增殖有抑制的效果，但對紅血球前驅細胞有增殖之影響，在分化7天後，較控制組提升了44%與52%，表面標誌物分析結果顯示，5α-THB與5β-THB能夠使得紅血球提早完成分化並維持高比例之CD71+D235a+，血紅蛋白濃度分析則證明，添加5α-THB與5β-THB能夠使分化第7天之細胞達到與全血離心之紅血球細胞相同之血紅蛋白濃度。
綜上所述，本研究致力研究小分子藥物對造血幹細胞增殖與紅血球分化之影響，對於解決全球血液短缺問題，具有重要的應用價值和潛在的臨床意義。

Recent research has explored various techniques, such as inducing pluripotent stem cells and embryonic stem cells, to proliferate red blood cells. However, challenges persist due to low rates of growth and inadequate hemoglobin levels.Consequently, studies focus on developing a culture medium for red blood cell differentiation using cytokines or small molecule drugs. This approach offers advantages such as good membrane permeability, low immunogenicity, and cost-effectiveness. This study is divided into two phases. First, develop a serum-free culture medium for hematopoietic stem cells using four small molecule drugs (UM729, SR1, 5α-THB, and 5β-THB). The results indicated that UM729 and SR1 significantly increased hematopoietic stem cell proliferation by 15-fold, while also maintaining high levels of CD34+CD38-. 5α-THB and 5β-THB inhibited the proliferation of hematopoietic stem cells. Secondly, use a serum-free red blood cell differentiation culture medium with the concentrations selected in the first step. Results showed that 5α-THB and 5β-THB positively impacted red blood cell proliferation and led to similar hemoglobin levels compared to whole blood.

[1] World Health Organization. Blood Safety and Availability. Available from: https://www.who.int/news-room/fact-sheets/detail/blood-safety-and-availability. 2023
[2] Trakarnsanga, K., et al., An Immortalized Adult Human Erythroid Line Facilitates Sustainable and Scalable Generation of Functional Red Cells. Nature Communications. 8(1): p. 14750. 2017
[3] Laurenti, E. and B. Göttgens, From Haematopoietic Stem Cells to Complex Differentiation Landscapes. Nature. 553(7689): p. 418-426. 2018
[4] Feng, Y., et al., Synthesis and Evaluation of Pyrimidoindole Analogs in Umbilical Cord Blood Ex Vivo Expansion. European Journal of Medicinal Chemistry. 174: p. 181-197. 2019
[5] Zhang, Y. and Y. Gao, Novel Chemical Attempts at Ex Vivo Hematopoietic Stem Cell Expansion. International Journal of Hematology. 103(5): p. 519-529. 2016
[6] Cong, Y.-S., W.E. Wright, and J.W. Shay, Human Telomerase and Its Regulation. Microbiology and Molecular Biology Reviews. 66(3): p. 407-425. 2002
[7] Alison, M.R., et al., An Introduction to Stem Cells. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland. 197(4): p. 419-423. 2002
[8] Baldwin, T., Morality and Human Embryo Research: Introduction to the Talking Point on Morality and Human Embryo Research. EMBO reports. 10(4): p. 299-300. 2009
[9] Takahashi, K. and S. Yamanaka, Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell. 126(4): p. 663-676. 2006
[10] Young, H.E. and A.C. Black Jr, Adult Stem Cells. The Anatomical Record Part A: Discoveries in Molecular, Cellular, and Evolutionary Biology 276(1): p. 75-102. 2004
[11] Mitalipov, S. and D. Wolf, Totipotency, Pluripotency and Nuclear Reprogramming. Engineering of Stem Cells. p. 185-199. 2009
[12] Schöler, H.R., Humanbiotechnology as Social Challenge. Routledge. 45-72. 2016
[13] Schugar, R., P. Robbins, and B. Deasy, Small Molecules in Stem Cell Self-Renewal and Differentiation. Gene Therapy. 15(2): p. 126-135. 2008
[14] Tseng, A.-S., F.B. Engel, and M.T. Keating, The Gsk-3 Inhibitor Bio Promotes Proliferation in Mammalian Cardiomyocytes. Chemistry & Biology. 13(9): p. 957-963. 2006
[15] Huang, X., et al., The Effects of the Wnt-Signaling Modulators Bio and Pkf118-310 on the Chondrogenic Differentiation of Human Mesenchymal Stem Cells. International Journal of Molecular Sciences. 19(2): p. 561. 2018
[16] Chen, J.K., et al., Small Molecule Modulation of Smoothened Activity. Proceedings of the National Academy of Sciences. 99(22): p. 14071-14076. 2002
[17] Chen, J.K., et al., Inhibition of Hedgehog Signaling by Direct Binding of Cyclopamine to Smoothened. Genes & Development. 16(21): p. 2743-2748. 2002
[18] Romer, J. and T. Curran, Targeting Medulloblastoma: Small-Molecule Inhibitors of the Sonic Hedgehog Pathway as Potential Cancer Therapeutics. Cancer Research. 65(12): p. 4975-4978. 2005
[19] Wu, X., et al., Purmorphamine Induces Osteogenesis by Activation of the Hedgehog Signaling Pathway. Chemistry & Biology. 11(9): p. 1229-1238. 2004
[20] Bellantuono, I., Haemopoietic Stem Cells. The international Journal of Biochemistry & Cell Biology. 36(4): p. 607-620. 2004
[21] Terstappen, L., et al., Sequential Generations of Hematopoietic Colonies Derived from Single Nonlineage-Committed Cd34+ Cd38-Progenitor Cells. bLOOD. 1991
[22] Yin, A.H., et al., Ac133, a Novel Marker for Human Hematopoietic Stem and Progenitor Cells. Blood. 90(12): p. 5002-5012. 1997
[23] Baum, C.M., et al., Isolation of a Candidate Human Hematopoietic Stem-Cell Population. Proceedings of the National Academy of Sciences. 89(7): p. 2804-2808. 1992
[24] Majeti, R., C.Y. Park, and I.L. Weissman, Identification of a Hierarchy of Multipotent Hematopoietic Progenitors in Human Cord Blood. Cell Stem Cell. 1(6): p. 635-645. 2007
[25] Notta, F., et al., Isolation of Single Human Hematopoietic Stem Cells Capable of Long-Term Multilineage Engraftment. Science. 333(6039): p. 218-221. 2011
[26] Boitano, A.E., et al., Aryl Hydrocarbon Receptor Antagonists Promote the Expansion of Human Hematopoietic Stem Cells. Science. 329(5997): p. 1345-1348. 2010
[27] Wagner, J.E., et al., Phase I/Ii Trial of Stemregenin-1 Expanded Umbilical Cord Blood Hematopoietic Stem Cells Supports Testing as a Stand-Alone Graft. Cell Stem Cell. 18(1): p. 144-155. 2016
[28] Fares, I., et al., Pyrimidoindole Derivatives Are Agonists of Human Hematopoietic Stem Cell Self-Renewal. Science. 345(6203): p. 1509-1512. 2014
[29] Cohen, S., et al., Hematopoietic Stem Cell Transplantation Using Single Um171-Expanded Cord Blood: A Single-Arm, Phase 1–2 Safety and Feasibility Study. The Lancet Haematology. 7(2): p. e134-e145. 2020
[30] Hua, P., et al., The Bet Inhibitor Cpi203 Promotes Ex Vivo Expansion of Cord Blood Long-Term Repopulating Hscs and Megakaryocytes. Blood. 136(21): p. 2410-2415. 2020
[31] Corrons, J.V., L.B. Casafont, and E.F. Frasnedo, Concise Review: How Do Red Blood Cells Born, Live, and Die? Annals of Hematology. 100(10): p. 2425-2433. 2021
[32] Cosgrove, J., et al., Hematopoiesis in Numbers. Trends in Immunology. 42(12): p. 1100-1112. 2021
[33] Allegraud, A., I. Dobo, and V. Praloran, Collagen Gel Culture of the Human Hematopoietic Progenitors Cfu-Gm, Cfu-E, and Bfu-E. Basic Cell Culture Protocols. p. 221-230. 1997
[34] Liu, J., et al., Quantitative Analysis of Murine Terminal Erythroid Differentiation in Vivo: Novel Method to Study Normal and Disordered Erythropoiesis. Blood. 121(8): p. e43-e49. 2013
[35] Jain, R.K. and D. Fukumura, Strategies in Regenerative Medicine, in Strategies in Regenerative Medicine: Integrating Biology with Materials Design. Springer. p. 1-41. 2008
[36] Moras, M., S.D. Lefevre, and M.A. Ostuni, From Erythroblasts to Mature Red Blood Cells: Organelle Clearance in Mammals. Front Physiol. 8: p. 1076. 2017
[37] Liu, J., et al., Membrane Remodeling During Reticulocyte Maturation. Blood. 115(10): p. 2021-2027. 2010
[38] Mohandas, N. and P.G. Gallagher, Red Cell Membrane: Past, Present, and Future. Blood. 112(10): p. 3939-3948. 2008
[39] Medical Labs. Normoblastic Erythropoiesis. Available from: https://www.medical-labs.net/normoblastic-erythropoiesis-3381/. 2016
[40] Zivot, A., et al., Erythropoiesis: Insights into Pathophysiology and Treatments in 2017. Molecular Medicine. 24: p. 1-15. 2018
[41] Li, J., et al., Isolation and Transcriptome Analyses of Human Erythroid Progenitors: Bfu-E and Cfu-E. Blood. 124(24): p. 3636-3645. 2014
[42] Gautier, E.-F., et al., Comprehensive Proteomic Analysis of Human Erythropoiesis. Cell Reports. 16(5): p. 1470-1484. 2016
[43] An, X. and L. Chen, Flow Cytometric Analysis of Erythroblast Enucleation. Erythropoiesis: Methods and Protocols. p. 193-203. 2018
[44] Kralik, P. and M. Ricchi, A Basic Guide to Real Time Pcr in Microbial Diagnostics: Definitions, Parameters, and Everything. Front Microbiol. 8: p. 108. 2017
[45] Bustin, S.A., et al., The Miqe Guidelines: M Inimum I Nformation for Publication of Q Uantitative Real-Time Pcr E Xperiments. Oxford University Press. 2009
[46] Ohneda, K. and M. Yamamoto, Roles of Hematopoietic Transcription Factors Gata-1 and Gata-2 in the Development of Red Blood Cell Lineage. Acta Haematologica. 108(4): p. 237-245. 2002
[47] Ferreira, R., et al., Gata1 Function, a Paradigm for Transcription Factors in Hematopoiesis. Molecular and Cellular Biology. 25(4): p. 1215-1227. 2005
[48] Siatecka, M. and J.J. Bieker, The Multifunctional Role of Eklf/Klf1 During Erythropoiesis. Blood. 118(8): p. 2044-2054. 2011
[49] Calabresi, L., M. Balliu, and N. Bartalucci, Immunoblotting-Assisted Assessment of Jak/Stat and Pi3k/Akt/Mtor Signaling in Myeloproliferative Neoplasms Cd34+ Stem Cells, in Methods in Cell Biology. Elsevier. p. 81-109. 2022
[50] Terszowski, G., et al., Prospective Isolation and Global Gene Expression Analysis of the Erythrocyte Colony-Forming Unit (Cfu-E). Blood. 105(5): p. 1937-1945. 2005
[51] Kaiho, S.-i. and K. Mizuno, Sensitive Assay Systems for Detection of Hemoglobin with 2, 7-Diaminofluorene: Histochemistry and Colorimetry for Erythrodifferentiation. Analytical Biochemistry. 149(1): p. 117-120. 1985
[52] Gebran, S., et al., A Modified Colorimetric Method for the Measurement of Phagocytosis and Antibody-Dependent Cell Cytotoxicity Using 2, 7-Diaminofluorene. Journal of Immunological Methods. 151(1-2): p. 255-260. 1992
[53] Manz, M.G., et al., Prospective Isolation of Human Clonogenic Common Myeloid Progenitors. Proceedings of the National Academy of Sciences. 99(18): p. 11872-11877. 2002
[54] Lee, S.-J., et al., Generation of Red Blood Cells from Human Pluripotent Stem Cells—an Update. Cells. 12(11): p. 1554. 2023
[55] Fibach, E., Erythropoiesis in Vitro—a Research and Therapeutic Tool in Thalassemia. Journal of Clinical Medicine. 8(12): p. 2124. 2019
[56] Chen, Y., et al., Mesenchymal Stromal Cells Can Be Applied to Red Blood Cells Storage as a Kind of Cellular Additive. Bioscience Reports. 37(5): p. BSR20170676. 2017
[57] Neildez-Nguyen, T.M.A., et al., Human Erythroid Cells Produced Ex Vivo at Large Scale Differentiate into Red Blood Cells in Vivo. Nature Biotechnology. 20(5): p. 467-472. 2002
[58] Giarratana, M.-C., et al., Ex Vivo Generation of Fully Mature Human Red Blood Cells from Hematopoietic Stem Cells. Nature Biotechnology. 23(1): p. 69-74. 2005
[59] Lu, S.-J., et al., Biologic Properties and Enucleation of Red Blood Cells from Human Embryonic Stem Cells. Blood. 112(12): p. 4475-4484. 2008
[60] Hirose, S.-i., et al., Immortalization of Erythroblasts by C-Myc and Bcl-Xl Enables Large-Scale Erythrocyte Production from Human Pluripotent Stem Cells. Stem Cell Reports. 1(6): p. 499-508. 2013
[61] Zhang, Y., et al., Large-Scale Ex Vivo Generation of Human Red Blood Cells from Cord Blood Cd34(+) Cells. Stem Cells Transl Med. 6(8): p. 1698-1709. 2017
[62] Deutsch, V.R. and A. Tomer, Megakaryocyte Development and Platelet Production. British Journal of Haematology. 134(5): p. 453-466. 2006
[63] Pineault, N. and G. Boisjoli, Megakaryopoiesis and Ex Vivo Differentiation of Stem Cells into Megakaryocytes and Platelets. ISBT Science Series. 10(S1): p. 154-162. 2015
[64] Cortin, V., N. Pineault, and A. Garnier, Ex Vivo Megakaryocyte Expansion and Platelet Production from Human Cord Blood Stem Cells. Stem cells in regenerative medicine. p. 109-126. 2009
[65] Mestrum, S.G., et al., The Potential of Proliferative and Apoptotic Parameters in Clinical Flow Cytometry of Myeloid Malignancies. Blood Advances. 5(7): p. 2040-2052. 2021
[66] Hamlett, I., et al., Characterization of Megakaryocyte Gata1-Interacting Proteins: The Corepressor Eto2 and Gata1 Interact to Regulate Terminal Megakaryocyte Maturation. Blood, The Journal of the American Society of Hematology. 112(7): p. 2738-2749. 2008
[67] Shivdasani, R.A., et al., Transcription Factor Nf-E2 Is Required for Platelet Formation Independent of the Actions of Thrombopoeitin/Mgdf in Megakaryocyte Development. Cell. 81(5): p. 695-704. 1995
[68] Pang, L., M.J. Weiss, and M. Poncz, Megakaryocyte Biology and Related Disorders. The Journal of Clinical Investigation. 115(12): p. 3332-3338. 2005
[69] Sekhon, S.S. and V. Roy, Thrombocytopenia in Adults: A Practical Approach to Evaluation and Management. Southern Medical Journal 99(5): p. 491. 2006
[70] Krishnegowda, M. and V. Rajashekaraiah, Platelet Disorders: An Overview. Blood Coagulation & Fibrinolysis. 26(5): p. 479-491. 2015
[71] 許鈴宜, et al., 2016 年台灣血小板輸用概況. 醫院雜誌. 52(2): p. 24-35. 2019
[72] Zauli, G., et al., In Vitro Senescence and Apoptotic Cell Death of Human Megakaryocytes. Blood. 90(6): p. 2234-2243. 1997
[73] Fujimoto, T.-T., et al., Production of Functional Platelets by Differentiated Embryonic Stem (Es) Cells in Vitro. Blood. 102(12): p. 4044-4051. 2003
[74] Takayama, N., et al., Transient Activation of C-Myc Expression Is Critical for Efficient Platelet Generation from Human Induced Pluripotent Stem Cells. Journal of Experimental Medicine. 207(13): p. 2817-2830. 2010
[75] Kobayashi, H., et al., Environmental Optimization Enables Maintenance of Quiescent Hematopoietic Stem Cells Ex Vivo. Cell Reports. 28(1): p. 145-158. e9. 2019
[76] Gstraunthaler, G., Alternatives to the Use of Fetal Bovine Serum: Serum-Free Cell Culture. ALTEX. 20(4): p. 275-281. 2003
[77] Yao, C.-L., et al., Factorial Designs Combined with the Steepest Ascent Method to Optimize Serum-Free Media for Ex Vivo Expansion of Human Hematopoietic Progenitor Cells. Enzyme and Microbial Technology. 33(4): p. 343-352. 2003
[78] Chen, C.B., et al., Overview of Albumin Physiology and Its Role in Pediatric Diseases. Current Gastroenterology Reports. 23(8): p. 11. 2021
[79] Karnieli, O., et al., A Consensus Introduction to Serum Replacements and Serum-Free Media for Cellular Therapies. Cytotherapy. 19(2): p. 155-169. 2017
[80] Dimitriadis, G., et al., Insulin Effects in Muscle and Adipose Tissue. Diabetes Research and Clinical Practice. 93: p. S52-S59. 2011
[81] Nelson, D.L., A.L. Lehninger, and M.M. Cox, Lehninger Principles of Biochemistry. Macmillan. 2008
[82] Lackie, J., A Dictionary of Biomedicine. Oxford Quick Reference. 2010
[83] Broudy, V.C., Stem Cell Factor and Hematopoiesis. Blood, The Journal of the American Society of Hematology. 90(4): p. 1345-1364. 1997
[84] McNiece, I., K. Langley, and K. Zsebo, The Role of Recombinant Stem Cell Factor in Early B Cell Development. Synergistic Interaction with Il-7. Journal of Immunology. 146(11): p. 3785-3790. 1991
[85] Tsapogas, P., et al., In Vivo Evidence for an Instructive Role of Fms-Like Tyrosine Kinase-3 (Flt3) Ligand in Hematopoietic Development. Haematologica. 99(4): p. 638. 2014
[86] Karsunky, H., et al., Flt3 Ligand Regulates Dendritic Cell Development from Flt3+ Lymphoid and Myeloid-Committed Progenitors to Flt3+ Dendritic Cells in Vivo. The Journal of Experimental Medicine. 198(2): p. 305-313. 2003
[87] Kaushansky, K., Lineage-Specific Hematopoietic Growth Factors. New England Journal of Medicine. 354(19): p. 2034-2045. 2006
[88] de Graaf, C.A. and D. Metcalf, Thrombopoietin and Hematopoietic Stem Cells. Cell Cycle. 10(10): p. 1582-1589. 2011
[89] Guthridge, M.A., et al., Mechanism of Activation of the Gm-Csf, Il-3, and Il-5 Family of Receptors. Stem Cells. 16(5): p. 301-313. 1998
[90] Erta, M., A. Quintana, and J. Hidalgo, Interleukin-6, a Major Cytokine in the Central Nervous System. International journal of Biological Sciences. 8(9): p. 1254. 2012
[91] Koller, M.R., et al., Expansion of Primitive Human Hematopoietic Progenitors in a Perfusion Bioreactor System with Il-3, Il-6, and Stem Cell Factor. Biotechnology. 11(3): p. 358-363. 1993
[92] Hansen, P.J., K.B. Dobbs, and A.C. Denicol, Programming of the Preimplantation Embryo by the Embryokine Colony Stimulating Factor 2. Animal Reproduction Science. 149(1-2): p. 59-66. 2014
[93] Gasson, J.C., Molecular Physiology of Granulocyte-Macrophage Colony-Stimulating Factor. Blood. 1991
[94] Demetri, G.D. and J.D. Griffin, Granulocyte Colony-Stimulating Factor and Its Receptor. Blood. 1991
[95] Shimizu, K., et al., Aml1-Mtg8 Leukemic Protein Induces the Expression of Granulocyte Colony-Stimulating Factor (G-Csf) Receptor through the up-Regulation of Ccaat/Enhancer Binding Protein Epsilon. Blood. 96(1): p. 288-296. 2000
[96] Youssoufian, H., et al., Structure, Function, and Activation of the Erythropoietin Receptor. Blood. 1993
[97] Kuhikar, R., et al., Transforming Growth Factor Β1 Accelerates and Enhances in Vitro Red Blood Cell Formation from Hematopoietic Stem Cells by Stimulating Mitophagy. Stem Cell Research & Therapy. 11: p. 1-15. 2020
[98] Burbach, K.M., A. Poland, and C.A. Bradfield, Cloning of the Ah-Receptor Cdna Reveals a Distinctive Ligand-Activated Transcription Factor. Proceedings of the National Academy of Sciences. 89(17): p. 8185-8189. 1992
[99] Fukunaga, B.N., et al., Identification of Functional Domains of the Aryl Hydrocarbon Receptor. Journal of Biological Chemistry. 270(49): p. 29270-29278. 1995
[100] Rothhammer, V. and F.J. Quintana, The Aryl Hydrocarbon Receptor: An Environmental Sensor Integrating Immune Responses in Health and Disease. Nature Reviews Immunology. 19(3): p. 184-197. 2019
[101] Baba, T., et al., Structure and Expression of the Ah Receptor Repressor Gene. Journal of Biological Chemistry. 276(35): p. 33101-33110. 2001
[102] Giannone, J.V., et al., Prolonged Depletion of Ah Receptor without Alteration of Receptor Mrna Levels after Treatment of Cells in Culture with 2, 3, 7, 8-Tetrachlorodibenzo-P-Dioxin. Biochemical Pharmacology. 55(4): p. 489-497. 1998
[103] Giannone, J.V., et al., Prolonged Depletion of Ah Receptor without Alteration of Receptor Mrna Levels after Treatment of Cells in Culture with 2, 3, 7, 8-Tetrachlorodibenzo-P-Dioxin. Biochemical Pharmacology. 55(4): p. 489-497. 1998
[104] Opitz, C.A., et al., The Complex Biology of Aryl Hydrocarbon Receptor Activation in Cancer and Beyond. Biochemical Pharmacology. p. 115798. 2023
[105] Torti, M.F., et al., The Aryl Hydrocarbon Receptor as a Modulator of Anti-Viral Immunity. Frontiers in Immunology. 12: p. 624293. 2021
[106] Gassmann, K., et al., Species-Specific Differential Ahr Expression Protects Human Neural Progenitor Cells against Developmental Neurotoxicity of Pahs. Environmental health perspectives. 118(11): p. 1571-1577. 2010
[107] Thiel, R., et al., Peri-and Postnatal Exposure to 2, 3, 7, 8-Tetrachlorodibenzo-P-Dioxin: Effects on Physiological Development, Reflexes, Locomotor Activity and Learning Behaviour in Wistar Rats. Archives of Toxicology. 69: p. 79-86. 1994
[108] Mukai, M., et al., Behavioral Rhythmicity of Mice Lacking Ahr and Attenuation of Light-Induced Phase Shift by 2, 3, 7, 8-Tetrachlorodibenzo-P-Dioxin. Journal of Biological Rhythms. 23(3): p. 200-210. 2008
[109] Gandhi, R., et al., Activation of the Aryl Hydrocarbon Receptor Induces Human Type 1 Regulatory T Cell–Like and Foxp3+ Regulatory T Cells. Nature immunology. 11(9): p. 846-853. 2010
[110] Tomblin, J.K. and T.B. Salisbury, Insulin Like Growth Factor 2 Regulation of Aryl Hydrocarbon Receptor in Mcf-7 Breast Cancer Cells. Biochemical and Biophysical Research Communications. 443(3): p. 1092-1096. 2014
[111] Larigot, L., et al., Ahr Signaling Pathways and Regulatory Functions. Biochimie Open. 7: p. 1-9. 2018
[112] García‐Lara, L., et al., Absence of Aryl Hydrocarbon Receptors Increases Endogenous Kynurenic Acid Levels and Protects Mouse Brain against Excitotoxic Insult and Oxidative Stress. Journal of Neuroscience Research. 93(9): p. 1423-1433. 2015
[113] Matsumura, F., The Significance of the Nongenomic Pathway in Mediating Inflammatory Signaling of the Dioxin-Activated Ah Receptor to Cause Toxic Effects. Biochemical Pharmacology. 77(4): p. 608-626. 2009
[114] Chen, Y., et al., Inhibition of Aryl Hydrocarbon Receptor Signaling Promotes the Terminal Differentiation of Human Erythroblasts. Journal of Molecular Cell Biology. 14(2): p. mjac001. 2022
[115] Higashi, T., et al., Strategies in Regenerative Medicine: Integrating Biology with Materials Design. Vol. 72. Springer. 865-874. 2007
[116] Melcangi, R.C., S. Giatti, and L.M. Garcia-Segura, Levels and Actions of Neuroactive Steroids in the Nervous System under Physiological and Pathological Conditions: Sex-Specific Features. Neuroscience & Biobehavioral Reviews. 67: p. 25-40. 2016
[117] Wu, P.-Y., et al., Novel Endogenous Ligands of Aryl Hydrocarbon Receptor Mediate Neural Development and Differentiation of Neuroblastoma. ACS Chemical Neuroscience. 10(9): p. 4031-4042. 2019
[118] Pabst, C., et al., Identification of Small Molecules That Support Human Leukemia Stem Cell Activity Ex Vivo. Nature Methods. 11(4): p. 436-442. 2014
[119] Singh, J., et al., Generation and Function of Progenitor T Cells from Stemregenin-1–Expanded Cd34+ Human Hematopoietic Progenitor Cells. Blood Advances. 3(20): p. 2934-2948. 2019
[120] van Grevenynghe, J.v., et al., Human Cd34-Positive Hematopoietic Stem Cells Constitute Targets for Carcinogenic Polycyclic Aromatic Hydrocarbons. Journal of Pharmacology and Experimental Therapeutics. 314(2): p. 693-702. 2005
[121] Smith, B.W., et al., The Aryl Hydrocarbon Receptor Directs Hematopoietic Progenitor Cell Expansion and Differentiation. Blood. 122(3): p. 376-385. 2013
[122] Leung, A., et al., Notch and Aryl Hydrocarbon Receptor Signaling Impact Definitive Hematopoiesis from Human Pluripotent Stem Cells. Stem Cells. 36(7): p. 1004-1019. 2018
[123] Bustin, S.A., A-Z of Quantitative Pcr. Vol. 29. International University Line. 2004
[124] Mackay, I.M., K.E. Arden, and A. Nitsche, Real-Time Pcr in Virology. Nucleic Acids Research. 30(6): p. 1292-1305. 2002
[125] Sambrook, J., E.F. Fritsch, and T. Maniatis, Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory Press. 1989
[126] Livak, K.J. and T.D. Schmittgen, Analysis of Relative Gene Expression Data Using Real-Time Quantitative Pcr and the 2− Δδct Method. Methods. 25(4): p. 402-408. 2001
[127] Barbas, C.F., et al., Quantitation of DNA and Rna. Cold Spring Harbor Protocols. 2007(11): p. pdb. ip47. 2007
[128] Franken, N.A., et al., Clonogenic Assay of Cells in Vitro. Nature Protocols. 1(5): p. 2315-2319. 2006
[129] Fracchiolla, N.S., et al., Dioxin Exposure of Human Cd34+ Hemopoietic Cells Induces Gene Expression Modulation That Recapitulates Its in Vivo Clinical and Biological Effects. Toxicology. 283(1): p. 18-23. 2011