한빛사논문
- 조회1,173
Tae-Yoon Park 1,2,8, Jeha Jeon 1,2,8, Nayeon Lee 1,2, Jisun Kim 1,2, Bin Song 1,2, Jung-Ho Kim 3, Sang-Kyou Lee 3,4, Dongxin Liu 1,2, Young Cha 1,2, Minseon Kim 1,2, Pierre Leblanc 1,2, Todd M. Herrington 5, Bob S. Carter 6, Jeffrey S. Schweitzer 6 & Kwang-Soo Kim 1,2,6,7,*
1Molecular Neurobiology Laboratory, Department of Psychiatry and McLean Hospital, Harvard Medical School, Belmont, MA, USA.
2Program in Neuroscience, Harvard Medical School, Belmont, MA, USA.
3Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
4Good T Cells, Inc., Seoul, Republic of Korea.
5Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
6Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
7Harvard Stem Cell Institute, Harvard Medical School, Belmont, MA, USA.
8These authors contributed equally: Tae-Yoon Park, Jeha Jeon.
*Corresponding author: correspondence to Kwang-Soo Kim
Abstract
The specific loss of midbrain dopamine neurons (mDANs) causes major motor dysfunction in Parkinson’s disease, which makes cell replacement a promising therapeutic approach. However, poor survival of grafted mDANs remains an obstacle to successful clinical outcomes. Here we show that the surgical procedure itself (referred to here as ‘needle trauma’) triggers a profound host response that is characterized by acute neuroinflammation, robust infiltration of peripheral immune cells and brain cell death. When midbrain dopamine (mDA) cells derived from human induced pluripotent stem (iPS) cells were transplanted into the rodent striatum, less than 10% of implanted tyrosine hydroxylase (TH)+ mDANs survived at two weeks after transplantation. By contrast, TH− grafted cells mostly survived. Notably, transplantation of autologous regulatory T (Treg) cells greatly modified the response to needle trauma, suppressing acute neuroinflammation and immune cell infiltration. Furthermore, intra-striatal co-transplantation of Treg cells and human-iPS-cell-derived mDA cells significantly protected grafted mDANs from needle-trauma-associated death and improved therapeutic outcomes in rodent models of Parkinson’s disease with 6-hydroxydopamine lesions. Co-transplantation with Treg cells also suppressed the undesirable proliferation of TH− grafted cells, resulting in more compact grafts with a higher proportion and higher absolute numbers of TH+ neurons. Together, these data emphasize the importance of the initial inflammatory response to surgical injury in the differential survival of cellular components of the graft, and suggest that co-transplanting autologous Treg cells effectively reduces the needle-trauma-induced death of mDANs, providing a potential strategy to achieve better clinical outcomes for cell therapy in Parkinson’s disease.
논문정보
- Research article
- 2023년 07월 (BRIC 등록일 2023-07-17)
- 국내+국외 연구진
- 생명과학 > 신경생물학
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