Developing the differentiation methods from pluripotent stem cells to glomerular endothelial cells for diabetic research

• Project/Area Number: 19K23933
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: Tohoku University
• Principal Investigator: Toyohara Takafumi 東北大学, 医工学研究科, 特任助教 (60594182)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 内皮細胞 / iPS細胞 / 腎臓 / 糸球体 / ES細胞 / 多能性幹細胞 / 糖尿病

Outline of Research at the Start

糖尿病による腎障害に対する有効な治療法は未だ開発されていない。糖尿病性腎症発症において早期に機能不全に陥る細胞の一つとして糸球体内皮細胞が知られているが糸球体内皮細胞に機能不全が生じるメカニズムについては十分に解明されていない。そこで本研究ではヒトの様々な細胞に分化できるヒト多能性幹細胞からヒト糸球体内皮細胞を作製し、糖尿病性腎症のにおける糸球体内皮障害の解明と治療開発を促進することを目的とする。

Outline of Final Research Achievements

In this project, we aimed to establish differentiation methods from pluripotent stem cells to glomerular endothelial cells for developing new therapy against diabetic nephropathy. We screened some growth factors existing at glomerulus that increase the expression of DKK2, one of the potential markers for glomerular endothelial cells. Some factors induced DKK2 when they were added at the late time point of the previous differentiation method (Patsch et al. Nat Cell Biol., 2015). Some factors also synergistically induced DKK2. DKK2 expression was more upregulated on the laminin 512-coating plate.

Academic Significance and Societal Importance of the Research Achievements

ヒト多能性幹細胞は様々な組織や細胞にも分化することが可能で、無限に増殖することができる。本研究成果をさらに発展させてヒト腎臓にある糸球体内皮細胞が作製可能となれば、糖尿病性腎症をはじめその他の腎症の病態解明や薬剤スクリーニングが飛躍的に進むことが期待される。また腎疾患に対する細胞移植療法の材料となる可能性も将来的には考えられる。

Research Products

• [Int'l Joint Research] Beth Israel Deaconess Medical Center(米国)
• [Journal Article] Treatment of Refractory Hypertension with Timely Angioplasty in Total Renal Artery Occlusion with Atrophic Kidney (2021)
  • Author(s): Sasaki Yuri、Mishima Eikan、Kikuchi Koichi、Toyohara Takafumi、Suzuki Takehiro、Ota Hideki、Seiji Kazumasa、Miyazaki Mariko、Harigae Hideo、Ito Sadayoshi、Takase Kei、Abe Takaaki
  • Journal Title: Internal Medicine Volume: 60 Issue: 2 Pages: 287-292
  • DOI: 10.2169/internalmedicine.5290-20
  • NAID: 130007968948
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-01-15
  • Peer Reviewed / Open Access
• [Journal Article] L-type amino acid transporter 1 is associated with chemoresistance in breast cancer via the promotion of amino acid metabolism (2021)
  • Author(s): Sato Miku、Harada-Shoji Narumi、Toyohara Takafumi、Soga Tomoyoshi、Itoh Masatoshi、Miyashita Minoru、Tada Hiroshi、Amari Masakazu、Anzai Naohiko、Furumoto Shozo、Abe Takaaki、Suzuki Takashi、Ishida Takanori、Sasano Hironobu
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 589-589
  • DOI: 10.1038/s41598-020-80668-5
  • Peer Reviewed / Open Access
• [Journal Article] Apparent Diffusion Coefficient in the Resolution of Renal Ischemia after Angioplasty on Diffusion-weighted Imaging: Renal Artery Stenosis Caused by Progressive Thrombosis in Residual Chronic Aortic Dissection (2020)
  • Author(s): Mishima Eikan、Ota Hideki、Suzuki Takehiro、Toyohara Takafumi、Seiji Kazumasa、Ito Sadayoshi、Saiki Yoshikatsu、Takase Kei、Abe Takaaki
  • Journal Title: Internal Medicine Volume: 59 Issue: 9 Pages: 1173-1177
  • DOI: 10.2169/internalmedicine.3855-19
  • NAID: 130007839437
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-05-01
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5 (2020)
  • Author(s): Oikawa Yoshitsugu、Izumi Rumiko、Koide Masashi、、、Aoki Masashi、Kure Shigeo、Abe Takaaki
  • Journal Title: PLOS ONE Volume: 15 Issue: 12 Pages: e0231064-e0231064
  • DOI: 10.1371/journal.pone.0231064
  • Peer Reviewed / Open Access
• [Journal Article] Germ-free conditions modulate host purine metabolism, exacerbating adenine-induced kidney damage. (2020)
  • Author(s): Mishima E, Ishijo M, Kawabe T, Kikuchi K, Akiyama Y, Toyohara T, Suzuki C, Asao A, Ishii N, Fukuda S, Abe T
  • Journal Title: Toxins Volume: 12 Issue: 9 Pages: 547-547
  • DOI: 10.3390/toxins12090547
  • Peer Reviewed / Open Access
• [Journal Article] Concurrent analogous organ damage in the brain, eyes, and kidneys in malignant hypertension: reversible encephalopathy, serous retinal detachment, and proteinuria (2020)
  • Author(s): Mishima E, Funayama Y, Suzuki T, Mishima F, Nitta F, Toyohara T, Kikuchi K, Kunikata H, Hashimoto J, Miyazaki M, Harigae H, Nakazawa T, Ito S, Abe T.
  • Journal Title: Hypertension Research Volume: 44 Issue: 1 Pages: 88-97
  • DOI: 10.1038/s41440-020-0521-2
  • Peer Reviewed / Open Access
• [Journal Article] Patient hiPSCs Identify Vascular Smooth Muscle Arylacetamide Deacetylase as Protective against Atherosclerosis (2020)
  • Author(s): Toyohara Takafumi、Roudnicky Filip、Florido Mary H.C.、Nakano Toshiaki、Yu Haojie、Katsuki Shunsuke、Lee Minjin、Meissner Torsten、Friesen Max、Davidow Lance S.、Ptaszek Leon、Abe Takaaki、Rubin Lee L.、Pereira Alexandre C.、Aikawa Masanori、Cowan Chad A.
  • Journal Title: Cell Stem Cell Volume: 27 Issue: 1 Pages: 147-157.e7
  • DOI: 10.1016/j.stem.2020.04.018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Kidney enlargement effect of angioplasty for nonatherosclerotic renovascular disease: reversibility of ischemic kidney (2020)
  • Author(s): Iwasaki Tomoyuki、Mishima Eikan、Suzuki Takehiro、Kikuchi Koichi、Toyohara Takafumi、Seiji Kazumasa、Takase Kei、Miyazaki Mariko、Harigae Hideo、Ito Sadayoshi、Abe Takaaki
  • Journal Title: Hypertension Research Volume: 43 Issue: 11 Pages: 1214-1221
  • DOI: 10.1038/s41440-020-0473-6
  • Peer Reviewed / Open Access
• [Journal Article] A nonhuman primate model of liver fibrosis towards cell therapy for liver cirrhosis. (2020)
  • Author(s): Yasuda K, Kotaka M, Toyohara T, Sueta SI, Katakai Y, Ageyama N, Uemoto S, Osafune K.
  • Journal Title: Biochem Biophys Res Commun Volume: 20 Issue: 3 Pages: 30643-30644
  • DOI: 10.1016/j.bbrc.2020.03.148
  • Peer Reviewed / Open Access
• [Journal Article] Mitoregulin Controls β-Oxidation in Human and Mouse Adipocytes. (2020)
  • Author(s): Friesen M, Warren CR, Yu H, Toyohara T, Ding Q, Florido MHC, Sayre C, Pope BD, Goff LA, Rinn JL, Cowan CA.
  • Journal Title: Stem Cell Reports Volume: 14 Issue: 4 Pages: 590-602
  • DOI: 10.1016/j.stemcr.2020.03.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HPRT-related hyperuricemia with a novel p.V35M mutation in HPRT1 presenting familial juvenile gout. (2020)
  • Author(s): Mishima E, Mori T, Nakajima Y, Toyohara T, Kikuchi K, Oikawa Y, Matsuhashi T, Maeda Y, Suzuki T, Kudo M, Ito S, Sohara E, Uchida S, Abe T.
  • Journal Title: CEN Case Rep Volume: pub Issue: 3 Pages: 210-214
  • DOI: 10.1007/s13730-020-00459-9
  • Peer Reviewed / Open Access
• [Journal Article] GPR146 Deficiency Protects against Hypercholesterolemia and Atherosclerosis (2019)
  • Author(s): Yu H、Rimbert A、Palmer AE.、Toyohara T、Xia Y、Xia F、Ferreira LMR.、Chen Z、Chen T、Loaiza N、Horwitz NB、Kacergis Michael C、Zhao L、Soukas AA.、Kuivenhoven JA、Kathiresan S、Cowan CA.
  • Journal Title: Cell Volume: 179 Issue: 6 Pages: 1276-1288.e14
  • DOI: 10.1016/j.cell.2019.10.034
  • Peer Reviewed