Deciphering the aging mechanism directed by exosomes in the adult progeria Werner syndrome

• Project/Area Number: 20K16542
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Chiba University
• Principal Investigator: Kato Hisaya 千葉大学, 医学部附属病院, 助教 (90841974)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 早老症 / 老化 / ウェルナー症候群 / 間葉系幹細胞 / iPS細胞 / エクソソーム

Outline of Research at the Start

遺伝性早老症ウェルナー症候群は、一般的なヒトの老化に見られるような症状(白内障、糖尿病、悪性腫瘍など)を若年で呈する一方、間葉系組織を中心とした臓器に、一般老化では見られないような特有の症状(難治性皮膚潰瘍、肉腫など)を呈するが、その原因は明らかではない。本研究では、患者を苦しめる主要な要因の一つである難治性皮膚潰瘍に焦点を当て、老化関連エクソソームとの関連について研究を進める。

Outline of Final Research Achievements

Werner syndrome (WS) is an autosomal recessive premature aging disorder that causes gray hair, hair loss, cataracts, diabetes, dyslipidemia, atherosclerotic disease, and malignant tumors from a young age. WS patients are also characterized by calcification of Achilles tendons and soft tissues and intractable skin ulcers, but no fundamental treatment has yet been established. Abnormalities of mesenchymal stem cells (MSCs) are suspected to be responsible for these symptoms, but the effect of WS-derived MSCs on skin ulcers is unknown. In this study, iPS cells derived from WS patients were differentiated into MSCs and injected into mouse models of skin ulcers, and we found that WS-MSCs have inferior wound-healing ability compared to healthy MSCs. Additionally, the wound healing ability of WS-MSCs was improved by mixed administration with VEGF. These findings are expected to be applied to the elucidation of pathological conditions and therapeutic applications in the future.

Academic Significance and Societal Importance of the Research Achievements

本研究では、ウェルナー症候群患者から樹立したiPS細胞から分化させた間葉系幹細胞が、早期細胞老化を示すこと、分泌因子に異常をきたすこと、中でも血管新生に大きな影響を持つVEGFの異常が疑われることを明らかにした。VEGFとウェルナー症候群間葉系幹細胞の混合投与が難治性皮膚潰瘍モデルマウスの創傷治癒を促進させたことから、分泌因子を中心とした病態メカニズムやこれらをターゲットとした治療応用へと発展させることが期待できる。

Research Products

• [Journal Article] Atherosclerosis and Cardiovascular Diseases in Progeroid Syndromes (2022)
  • Author(s): Kato Hisaya、Maezawa Yoshiro
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 29 Issue: 4 Pages: 439-447
  • DOI: 10.5551/jat.RV17061
  • NAID: 130008086716
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2022-04-01
  • Peer Reviewed / Open Access
• [Journal Article] Generation of disease-specific and CRISPR/Cas9-mediated gene-corrected iPS cells from a patient with adult progeria Werner syndrome (2021)
  • Author(s): Kato Hisaya、Maezawa Yoshiro、Ouchi Yasuo、Takayama Naoya、Sone Masamitsu、Sone Kanako、Takada-Watanabe Aki、Tsujimura Kyoko、Koshizaka Masaya、Nagasawa Sayaka、Saitoh Hisako、Ohtaka Manami、Nakanishi Mahito、Tahara Hidetoshi、Shimamoto Akira、Iwama Atsushi、Eto Koji、Yokote Koutaro
  • Journal Title: Stem Cell Research Volume: 53 Pages: 102360-102360
  • DOI: 10.1016/j.scr.2021.102360
  • Peer Reviewed / Open Access
• [Journal Article] Fibroblasts from different body parts exhibit distinct phenotypes in adult progeria Werner syndrome (2021)
  • Author(s): Kato H, Maezawa Y, Takayama N, Ouchi Y, Kaneko H, Kinoshita D, Takada-Watanabe A, Oshima M, Koshizaka M, Ogata H, Kubota Y, Mitsukawa N, Eto K, Iwama A, Yokote K.
  • Journal Title: Aging (Albany NY) Volume: 13 Issue: 4 Pages: 4946-4961
  • DOI: 10.18632/aging.202696
  • Peer Reviewed / Open Access