Cutting edge Seminar
Speaker: Hidetaka Suga (Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine)
Title: Cell therapy for hypopituitarism
※This seminar can also be attended through ZOOM. Please check the URL on “HIGO Cutting-Edge Seminar” at Moodle.
https://md.kumamoto-u.ac.jp/course/view.php?id=114380
Abstract:
The hypothalamic-pituitary system is essential for maintaining homeostasis and life by regulating systemic hormones. Disorders of the hypothalamus-pituitary system do not recover, and treatment requires replacement of deficient hormones. However, this hormone replacement therapy is sometimes difficult to replenish adequately, and even with current treatments, life expectancy, complications and quality of life remain problematic. The reason is that hormone production should be adjusted in response to the surrounding environment, but the current treatment is unable to respond to fluctuations in demand, resulting in a gap between supply and demand. If responsive hormone-producing cells could be produced, the possibility of achieving a higher level of homeostasis would arise, which could lead to a new therapeutic approach.
Tissue stem cells in this area have been intensively studied, but at present they are not yet clearly defined. Nor do they have a high actual regenerative capacity. This is where pluripotent stem cells, such as embryonic stem (ES) cells and induced pluripotent stem (iPS) cells come into the practice. As they are pluripotent, they have the potential to differentiate in any directions. Therefore, it is important to establish a methodology to properly differentiate them into the target tissue.
We use a three-dimensional culture technique developed by the late Dr Yoshiki Sasai and his colleagues, enabling highly efficient induction of neural ectodermal cells of the head. Based on this, we have tried to follow the developmental rules of the hypothalamus and anterior pituitary. The key is not to force the expression of any factor, but to modify the conditions of the culture medium and to allow the cells to self-organize according to the developmental steps. In particular, in the differentiation method for the anterior pituitary, we focused on the fact that the anterior pituitary does not differentiate alone, but differentiates in relation to the hypothalamic neurons, and created conditions that allow simultaneous induction of hypothalamic neurons and anterior pituitary, even in vitro. In other words, it was confirmed that hypothalamic-like tissue and oral ectoderm-like tissue interact with each other to form the pituitary primordium in three-dimensional cell masses induced from ES/iPS cells, as in embryonic development. This can be regarded as a model for organogenesis and shows that organs can be formed in vitro as a result of the complex three-dimensional structure of multiple cell types and the chain interactions between cells. In addition, although it seems simpler and more efficient to differentiate only the anterior pituitary gland, the co-localization of neighboring hypothalamic neurons has been found to be important for final maturation. The results show that the secretory capacity per cell is equivalent to that of the adult and that there is functional cooperation between the hypothalamus and pituitary.
We have focused on this hypothalamic-pituitary system and have developed differentiation methods using mouse ES cells, human ES cells and human iPS cells, in that order. Currently, we are working on pathological analysis of genetic diseases, drug screening and the development of regenerative medicine cell preparations for transplantation.
Reference:
1) Self-formation of functional adenohypophysis in three-dimensional culture.
Suga H, Kadoshima T, Minaguchi M, Ohgushi M, Soen M, Nakano T, Takata N, Wataya T, Muguruma K, Miyoshi H, Yonemura S, Oiso Y, Sasai Y.
Nature. 2011 Nov 9;480(7375):57-62. doi: 10.1038/nature10637.
2) Functional anterior pituitary generated in self-organizing culture of human embryonic stem cells.
Ozone C, Suga H, Eiraku M, Kadoshima T, Yonemura S, Takata N, Oiso Y, Tsuji T, Sasai Y.
Nat Commun. 2016 Jan 14;7:10351. doi: 10.1038/ncomms10351.
3) Congenital pituitary hypoplasia model demonstrates hypothalamic OTX2 regulation of pituitary progenitor cells.
Matsumoto R, Suga H, Aoi T, Bando H, Fukuoka H, Iguchi G, Narumi S, Hasegawa T, Muguruma K, Ogawa W, Takahashi Y.
J Clin Invest. 2020 Feb 3;130(2):641-654. doi: 10.1172/JCI127378.
4) Hypothalamic Contribution to Pituitary Functions Is Recapitulated In Vitro Using 3D-Cultured Human iPS Cells.
Kasai T, Suga H, Sakakibara M, Ozone C, Matsumoto R, Kano M, Mitsumoto K, Ogawa K, Kodani Y, Nagasaki H, Inoshita N, Sugiyama M, Onoue T, Tsunekawa T, Ito Y, Takagi H, Hagiwara D, Iwama S, Goto M, Banno R, Takahashi J, Arima H.
Cell Rep. 2020 Jan 7;30(1):18-24.e5. doi: 10.1016/j.celrep.2019.12.009.
5) Generation of hypothalamic neural stem cell-like cells in vitro from human pluripotent stem cells.
Miwata T, Suga H, Kawaguchi Y, Sakakibara M, Kano M, Taga S, Soen M, Ozaki H, Asano T, Sasaki H, Miyata T, Yasuda Y, Kobayashi T, Sugiyama M, Onoue T, Takagi H, Hagiwara D, Iwama S, Arima H.
Stem Cell Reports. 2023 Apr 11;18(4):869-883. doi: 10.1016/j.stemcr.2023.02.006. Epub 2023 Mar 23.
6) Generation and purification of ACTH-secreting hPSC-derived pituitary cells for effective transplantation.
Taga S, Suga H, Nakano T, Kuwahara A, Inoshita N, Kodani Y, Nagasaki H, Sato Y, Tsumura Y, Sakakibara M, Soen M, Miwata T, Ozaki H, Kano M, Watari K, Ikeda A, Yamanaka M, Takahashi Y, Kitamoto S, Kawaguchi Y, Miyata T, Kobayashi T, Sugiyama M, Onoue T, Yasuda Y, Hagiwara D, Iwama S, Tomigahara Y, Kimura T, Arima H.
Stem Cell Reports. 2023 Aug 8;18(8):1657-1671. doi: 10.1016/j.stemcr.2023.05.002. Epub 2023 Jun 8.
