Generation of erythropoietin-producing cells derived from human iPSCs

• Project/Area Number: 24591204
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Kagawa University
• Principal Investigator: HITOMI Hirofumi 香川大学, 医学部, 助教 (70346641)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 再生医学 / 移植・再生医療 / iPS細胞 / エリスロポエチン / 腎性貧血

Outline of Final Research Achievements

We established a method to generate erythropoietin (EPO)-producing cells from human induced pluripotent stem cells (hiPSCs) that showed increased EPO expression and secretion in response to low oxygen conditions. The EPO protein secreted from hiPSC-derived EPO-producing cells (hiPSC-EPO cells) induced the erythropoietic differentiation of umbilical cord blood progenitors in vitro. Furthermore, injection of EPO protein from hiPSC-EPO cells improved renal anemia in adenine-induced renal failure mice. In conclusion, hiPSC-EPO cells may provide a novel therapeutic agent for anemia.

Research Products

• [Journal Article] Functional Analysis of iPSC-derived Myocytes from a Patient with Carnitine Palmitoyltransferase II Deficiency (2014)
  • Author(s): Tetsuhiko Yasuno, Kenji Osafune, Hidetoshi Sakurai, Isao Asaka, Akihito Tanaka, Seiji Yamaguchi, Kenji Yamada, Hirofumi Hitomi, Sayaka Arai, Yuko Kurose, Yasuki Higaki, Mizuki Sudo, Souichi Ando, Hitoshi Nakashima, Takao Saito, Hidetoshi Kaneoka
  • Journal Title: Biochem. and Biophys. Res. Commun Volume: (in press) Issue: 2 Pages: 175-181
  • DOI: 10.1016/j.bbrc.2014.04.084
  • Peer Reviewed / Open Access
• [Journal Article] High sodium augments angiotensin II-induced vascular smooth muscle cell proliferation through the ERK 1/2-dependent pathway. (2014)
  • Author(s): Liu G, Hitomi H, Rahman A, Nakano D, Mori H, Masaki T, Ma H, Iwamoto T, Kobori H, Nishiyama A.
  • Journal Title: Hypertens Res. Volume: 37(1) Issue: 1 Pages: 13-8
  • DOI: 10.1038/hr.2013.108
  • Peer Reviewed
• [Journal Article] Chymase activities and survival in endotoxin-induced human chymase transgenic mice. (2014)
  • Author(s): Rafiq K, Fan YY, Sherajee SJ, Takahashi Y, Matsuura J, Hase N, Mori H, Nakano D, Kobara H, Hitomi H, Masaki T, Urata H, Nishiyama A.
  • Journal Title: Int J Med Sci. Volume: 11 Issue: 3 Pages: 222-225
  • DOI: 10.7150/ijms.7382
  • Peer Reviewed
• [Journal Article] Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy. (2014)
  • Author(s): Kitada K, Nakano D, Ohsaki H, Hitomi H, Minamino T, Yatabe J, Felder RA, Mori H, Masaki T, Kobori H, Nishiyama A.
  • Journal Title: J Diabetes Complications Volume: 28 Issue: 5 Pages: 604-611
  • DOI: 10.1016/j.jdiacomp.2014.05.010
  • Peer Reviewed / Open Access
• [Journal Article] Chelation of dietary iron prevents iron accumulation and macrophage infiltration in the type I diabetic kidney. (2014)
  • Author(s): Morita T, Nakano D, Kitada K, Morimoto S, Ichihara A, Hitomi H, Kobori H, Shiojima I, Nishiyama A.
  • Journal Title: Eur J Pharmacol. Volume: 756 Pages: 85-91
  • DOI: 10.1016/j.ejphar.2015.03.053
  • Peer Reviewed
• [Journal Article] Role of (pro)renin receptor in angiotensin II-dependent and -independent EGF receptor transactivation. (2013)
  • Author(s): Shibayama Y, Hitomi H, Nakano D, Kobori H, Mori H, Deguchi K, Masaki T, Ichihara A, Nishiyama A.
  • Journal Title: Front Biosci Volume: E5:697-705 Issue: 2 Pages: 697-705
  • DOI: 10.2741/e650
  • Peer Reviewed
• [Journal Article] Aberrant activation of the intrarenal renin-angiotensin system in the developing kidneys of type 2 diabetic rats. (2013)
  • Author(s): Fan YY, Kobori H, Nakano D, Hitomi H, Mori H, Masaki T, Sun YX, Zhang L, Huang W, Zhu B, Li P, Nishiyama A.
  • Journal Title: Horm Metab Res. Volume: 45 Issue: 05 Pages: 338-343
  • DOI: 10.1055/s-0032-1331256
  • Peer Reviewed
• [Journal Article] Effects of Angiotensin II AT₁–Receptor Blockade on High Fat Diet–Induced Vascular Oxidative Stress and Endothelial Dysfunction in Dahl Salt-Sensitive Rats (2013)
  • Author(s): Kosaka S, Pelish N, Rahman M, Nakano D, Hitomi H, Kobori H, Fukuoka N, Kobara H, Mori H, Masaki T, Cervenka L, Matsumura Y, Houchi H, Nishiyama A.
  • Journal Title: Journal of Pharmacological Sciences Volume: 121 Issue: 2 Pages: 95-102
  • DOI: 10.1254/jphs.12169FP
  • NAID: 10031156938
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed
• [Journal Article] Angiotensin-Converting Enzyme Inhibitor Does Not Suppress Renal Angiotensin II Levels in Angiotensin I–Infused Rats (2013)
  • Author(s): Ohnishi K, Murase M, Nakano D, Pelisch N, Hitomi H, Kobori H, Morimoto S, Mori H, Masaki T, Ohmori K, Kohno M, Ichihara A, Nishiyama A.
  • Journal Title: Journal of Pharmacological Sciences Volume: 122 Issue: 2 Pages: 103-108
  • DOI: 10.1254/jphs.13045FP
  • NAID: 10031185402
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed
• [Journal Article] Roles of Na⁺/H⁺ Exchanger Type 1 and Intracellular pH in Angiotensin II-Induced Reactive Oxygen Species Generation and Podocyte Apoptosis (2013)
  • Author(s): Liu Y, Hitomi H, Diah S, Deguchi K, Mori H, Masaki T, Nakano D, Kobori H, Nishiyama A.
  • Journal Title: Journal of Pharmacological Sciences Volume: 122 Issue: 3 Pages: 176-183
  • DOI: 10.1254/jphs.12291FP
  • NAID: 10031185411
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed
• [Journal Article] Aldosterone aggravates glucose intolerance induced by high fructose. (2013)
  • Author(s): Sherajee SJ, Rafiq K, Nakano D, Mori H, Kobara H, Hitomi H, Fujisawa Y, Kobori H, Masaki T, Nishiyama A.
  • Journal Title: Eur J Pharmacol. Volume: 720(1-3) Issue: 1-3 Pages: 63-8
  • DOI: 10.1016/j.ejphar.2013.10.051
  • Peer Reviewed
• [Journal Article] Calcium channel blocker enhances beneficial effects of an angiotensin II AT1 receptor blocker against cerebrovascular-renal injury in type 2 diabetic mice. (2013)
  • Author(s): Rafiq K, Sherajee SJ, Hitomi H, Nakano D, Kobori H, Ohmori K, Mori H, Kobara H, Masaki T, Kohno M, Nishiyama A.
  • Journal Title: PLoS One. Volume: 8(12) Issue: 12 Pages: e82082-e82082
  • DOI: 10.1371/journal.pone.0082082
  • Peer Reviewed
• [Journal Article] Aldosterone Induces Vascular Insulin Resistance by Increasing Insulin-Like Growth Factor-1 Receptor and Hybrid Receptor. (2012)
  • Author(s): Sherajee SJ, Fujita Y, Rafiq K, Nakano D, Mori H, Masaki T, Hara T, Kohno M, Nishiyama A, Hitomi H.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 32 Issue: 2 Pages: 257-263
  • DOI: 10.1161/atvbaha.111.240697
  • Peer Reviewed
• [Journal Article] Early Treatment With Olmesartan Prevents Juxtamedullary Glomerular Podocyte Injury and the Onset of Microalbuminuria in Type 2 Diabetic Rats (2012)
  • Author(s): Sofue T, 他
  • Journal Title: Am J Hypertens Volume: 34(3)(In Press) Issue: 5 Pages: 604-11
  • DOI: 10.1038/ajh.2012.1
  • Peer Reviewed
• [Journal Article] Renal sympathetic denervation suppresses de novo podocyte injury and albuminuria in rats with aortic regurgitation. (2012)
  • Author(s): Rafiq K, Noma T, Fujisawa Y, Ishihara Y, Arai Y, Navi AHMN, Suzuki F,Nakano D, Hitomi H, Kitada K, Urushihara M, Kobori H, Kohno M, Nishiyama A.
  • Journal Title: Circulation. Volume: 125 Issue: 11 Pages: 1402-1413
  • DOI: 10.1161/circulationaha.111.064097
  • Peer Reviewed
• [Journal Article] Add-On Aliskiren Elicits Stronger Renoprotection Than High-Dose Valsartan in Type 2 Diabetic KKAy Mice That Do Not Respond to Low-Dose Valsartan (2012)
  • Author(s): Lei B, Nakano D, Fan YY, Kitada K, Hitomi H, Kobori H, Mori H, Masaki T, Nishiyama A.
  • Journal Title: Journal of Pharmacological Sciences Volume: 119 Issue: 2 Pages: 131-138
  • DOI: 10.1254/jphs.12031FP
  • NAID: 10030828408
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed
• [Journal Article] N-type Calcium Channel Inhibition With Cilnidipine Elicits Glomerular Podocyte Protection Independent of Sympathetic Nerve Inhibition (2012)
  • Author(s): Lei B, Nakano D, Fujisawa Y, Liu Y, Hitomi H, Kobori H, Mori H, Masaki T, Asanuma K, Tomino Y, Nishiyama A.
  • Journal Title: Journal of Pharmacological Sciences Volume: 119 Issue: 4 Pages: 359-367
  • DOI: 10.1254/jphs.12075FP
  • NAID: 10031071591
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed
• [Journal Article] Oxidative stress-induced glomerular mineralocorticoid receptor activation olimits the benefit of salt reduction in Dahl salt-sensitive rats (2012)
  • Author(s): K.Kitada, H.Shibata, et al.
  • Journal Title: PLoS One Volume: 7 Issue: 7 Pages: e41896-e41896
  • DOI: 10.1371/journal.pone.0041896
  • Peer Reviewed
• [Journal Article] Multiphoton Imaging of the Glomerular Permeability of Angiotensinogen. (2012)
  • Author(s): Nakano D, Kobori H, Burford JL, Gevorgyan H, Seidel S, Hitomi H, Nishiyama A, Peti-Peterdi J.
  • Journal Title: J Am Soc Nephrol Volume: 23 Issue: 11 Pages: 1847-1856
  • DOI: 10.1681/asn.2012010078
  • Peer Reviewed
• [Journal Article] Aldosterone induces p21-regulated apoptosis via increased synthesis and secretion of tumour necrosis factor-α in human proximal tubular cells. (2012)
  • Author(s): Kitada K, Nakano D, Hitomi H, Kobori H, Deguchi K, Mori H, Masaki T, Nishiyama A.
  • Journal Title: Clin Exp Pharmacol Physiol. Volume: 39(10) Issue: 10 Pages: 858-863
  • DOI: 10.1111/j.1440-1681.2012.12001.x
  • Peer Reviewed
• [Journal Article] Important Aspects of Urine Sampling for Angiotensinogen Measurement: Time and Preservation Conditions in Healthy Individuals (2012)
  • Author(s): Nishijima Y, Kobori H, Sofue T, Kaifu K, Moriwaki K, Hara T, Hitomi H, Kohno M, Nishiyama A.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 228 Issue: 4 Pages: 333-339
  • DOI: 10.1620/tjem.228.333
  • NAID: 10031135558
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed
• [Presentation] エリスロポエチン産生細胞による新しい治療の試み (2014)
  • Author(s): 西山 成、人見浩史、長船健二
  • Organizer: 第25回腎とフリーラジカル研究会
  • Place of Presentation: 東京都品川区
  • Year and Date: 2014-10-06
  • Invited
• [Presentation] Effects of erythropoietin originated by human ips cell-derived erythropoietin producing cells on adenine-induced renal anemia in mice. (2014)
  • Author(s): Rahman M, Hitomi H, Osafune K, Nishiyama A.
  • Organizer: The 14th Asian Pacific Congress of Nephrology
  • Place of Presentation: 東京都品川区
  • Year and Date: 2014-05-14 – 2014-05-17
• [Presentation] ヒトiPS細胞およびＥＳ細胞を用いたエリスロポエチン酸生細胞分化誘導法の確立 (2013)
  • Author(s): 人見浩史、笠原朋子、前 伸一、保科あずさ、小高真希、丹羽 明、齋藤 潤、中畑龍俊、西山 成、長船健二
  • Organizer: 第3回日本腎臓リハビリテーション学会学術集会
  • Place of Presentation: 栃木県宇都宮市
• [Presentation] iPS細胞およびＥＳ細胞を用いたエリスロポエチン産生細胞分化誘導法の確立 (2013)
  • Author(s): 人見浩史、笠原朋子、前 伸一、保科あずさ、小高真希、丹羽 明、齋藤 潤、中畑龍俊、西山 成、長船健二
  • Organizer: 第86回日本内分泌学会
  • Place of Presentation: 宮城県仙台市
• [Presentation] iPS細胞およびＥＳ細胞を用いたエリスロポエチン産生細胞分化誘導法の確立 (2013)
  • Author(s): 人見浩史、笠原朋子、前 伸一、保科あずさ、小高真希、丹羽 明、齋藤 潤、中畑龍俊、西山 成、長船健二
  • Organizer: 第56回日本腎臓学会学術総会
  • Place of Presentation: 東京都千代田区
• [Presentation] iPS細胞を用いた腎臓病治療の可能性 (2013)
  • Author(s): 人見浩史、西山 成、長船健二
  • Organizer: 平成２３年度香川県医学会
  • Place of Presentation: 香川県坂出市
  • Invited
• [Presentation] iPS細胞由来エリスロポエチン産生細胞の腎性貧血改善効果の検討 (2013)
  • Author(s): Asadur R, 人見浩史、笠原朋子、保科あずさ、小高真希、丹羽 明、齋藤 潤、中畑龍俊、西山 成、長船健二
  • Organizer: 第36回日本高血圧学会総会
  • Place of Presentation: 大阪府大阪市
• [Presentation] ヒトiPS細胞およびＥＳ細胞を用いたエリスロポエチン酸生細胞分化誘導法の確立 (2013)
  • Author(s): 人見浩史、笠原朋子、前 伸一、保科あずさ、小高真希、丹羽 明、齋藤 潤、中畑龍俊、西山 成、長船健二
  • Organizer: 第3回日本腎臓リハビリテーション学会
  • Place of Presentation: 栃木県宇都宮市
• [Presentation] 尿中アンジオテンシノージェン排泄量はメタボリック症候群患者におけるオルメサルタンの腎保護予測マーカーとなりうる (2012)
  • Author(s): 人見浩史、小堀浩幸、供田文宏、森本 聡、福井敏樹、長谷川浩一、中村 司、中野大介、河野雅和、西山 成
  • Organizer: 第35回日本高血圧学会総会
  • Place of Presentation: 愛知県名古屋市