The fate of iPSCs-derived low immunogenic dopaminergic neuron precursors after transplantation into the striatum of rats with 6-OHDA-induced parkinsonism
- Authors: Voronkov D.M.1, Lebedeva O.S.2, Stavrovskaya A.V.1, Bogomiakova M.E.2, Olshanskiy A.S.1, Kopylova I.V.2, Gushchina A.S.1, Simonova A.V.2, Ruchko E.S.2, Illarioshkin S.N.1, Eremeev A.V.2, Lagarkova M.A.2
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Affiliations:
- Research Center of Neurology Russian Academy of Sciences
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine
- Issue: Vol 18, No 4 (2023)
- Pages: 582-584
- Section: Conference proceedings
- URL: https://genescells.ru/2313-1829/article/view/623312
- DOI: https://doi.org/10.17816/gc623312
- ID: 623312
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Abstract
Parkinson’s disease arises from the demise of dopaminergic neurons in the substantia nigra resulting from both environmental and hereditary factors. Drug interventions can solely delay disease progression, but cannot provide a cure. Therefore, cell replacement therapy may represent a promising treatment approach. Although the United States has already employed this technology, independent clinical and preclinical trials are mandatory for its inclusion in Russia. The iPSC technology enables the acquisition of personalized iPSC lines for each patient, nearly eradicating the immune response. While autologous cell therapy is theoretically ideal, the reprogramming of patient cells into iPSCs and subsequent differentiation for each patient incurs time and cost. Alternatively, differentiated derivatives of low immunogenic iPSCs, lacking HLA class I expression, can serve as a substitute. These cells evade the T-cell immune response, but other minor HLAs and cells from the innate immune system, like macrophages and NK cells, could still participate in the immune response’s development, although not as potent as in allogeneic transplantation. While these cell products don’t escape the immune response entirely, they lessen it significantly, potentially enabling the use of less severe immunosuppressive therapy. In this study, a protocol previously established in the cell biology laboratory was used to differentiate iPSCs lacking HLA class I expression and wild-type iPSCs into midbrain dopaminergic neuron precursors. A thorough analysis of the forerunners was performed and demonstrated appropriate patterning. The progenitors were then implanted into the brains of rats with 6-OHDA-induced Parkinsonism and followed for 6 months to compare their in vivo differentiation to standard differentiation in vitro. In addition, the systemic inflammatory response of the animals to the transplantation and the biodistribution of the injected cells were investigated. The literature inadequately addresses the question of which cells, other than dopaminergic neurons, differentiate during in vivo graft differentiation and potentially cause side effects in cell therapy. The literature suggests that only approximately 3% of transplanted cells differentiate into dopaminergic neurons, which is adequate to improve motor function in model animals. We found that a significant proportion of the progenitors differentiate into glial cells. The dynamics of maturation of transplanted neurons was evaluated. Thus, we approached preclinical testing of the cell product after having characterized in detail the dynamics of maturation and the composition of the graft. Comparison of in vivo and in vitro differentiation will allow evaluation of the quality of cellular material for transplantation.
Full Text
Parkinson’s disease arises from the demise of dopaminergic neurons in the substantia nigra resulting from both environmental and hereditary factors. Drug interventions can solely delay disease progression, but cannot provide a cure. Therefore, cell replacement therapy may represent a promising treatment approach. Although the United States has already employed this technology, independent clinical and preclinical trials are mandatory for its inclusion in Russia. The iPSC technology enables the acquisition of personalized iPSC lines for each patient, nearly eradicating the immune response. While autologous cell therapy is theoretically ideal, the reprogramming of patient cells into iPSCs and subsequent differentiation for each patient incurs time and cost. Alternatively, differentiated derivatives of low immunogenic iPSCs, lacking HLA class I expression, can serve as a substitute. These cells evade the T-cell immune response, but other minor HLAs and cells from the innate immune system, like macrophages and NK cells, could still participate in the immune response’s development, although not as potent as in allogeneic transplantation. While these cell products don’t escape the immune response entirely, they lessen it significantly, potentially enabling the use of less severe immunosuppressive therapy. In this study, a protocol previously established in the cell biology laboratory was used to differentiate iPSCs lacking HLA class I expression and wild-type iPSCs into midbrain dopaminergic neuron precursors. A thorough analysis of the forerunners was performed and demonstrated appropriate patterning. The progenitors were then implanted into the brains of rats with 6-OHDA-induced Parkinsonism and followed for 6 months to compare their in vivo differentiation to standard differentiation in vitro. In addition, the systemic inflammatory response of the animals to the transplantation and the biodistribution of the injected cells were investigated. The literature inadequately addresses the question of which cells, other than dopaminergic neurons, differentiate during in vivo graft differentiation and potentially cause side effects in cell therapy. The literature suggests that only approximately 3% of transplanted cells differentiate into dopaminergic neurons, which is adequate to improve motor function in model animals. We found that a significant proportion of the progenitors differentiate into glial cells. The dynamics of maturation of transplanted neurons was evaluated. Thus, we approached preclinical testing of the cell product after having characterized in detail the dynamics of maturation and the composition of the graft. Comparison of in vivo and in vitro differentiation will allow evaluation of the quality of cellular material for transplantation.
ADDITIONAL INFORMATION
Acknowledgments. We thank the Center for Precision Editing and Genetic Technologies for Biomedicine for providing resources for this project.
About the authors
D. M. Voronkov
Research Center of Neurology Russian Academy of Sciences
Email: oslebedeva@rcpcm.org
Russian Federation, Moscow
O. S. Lebedeva
Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine
Author for correspondence.
Email: oslebedeva@rcpcm.org
Russian Federation, Moscow
A. V. Stavrovskaya
Research Center of Neurology Russian Academy of Sciences
Email: oslebedeva@rcpcm.org
Russian Federation, Moscow
M. E. Bogomiakova
Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine
Email: oslebedeva@rcpcm.org
Russian Federation, Moscow
A. S. Olshanskiy
Research Center of Neurology Russian Academy of Sciences
Email: oslebedeva@rcpcm.org
Russian Federation, Moscow
I. V. Kopylova
Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine
Email: oslebedeva@rcpcm.org
Russian Federation, Moscow
A. S. Gushchina
Research Center of Neurology Russian Academy of Sciences
Email: oslebedeva@rcpcm.org
Russian Federation, Moscow
A. V. Simonova
Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine
Email: oslebedeva@rcpcm.org
Russian Federation, Moscow
E. S. Ruchko
Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine
Email: oslebedeva@rcpcm.org
Russian Federation, Moscow
S. N. Illarioshkin
Research Center of Neurology Russian Academy of Sciences
Email: oslebedeva@rcpcm.org
Russian Federation, Moscow
A. V. Eremeev
Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine
Email: oslebedeva@rcpcm.org
Russian Federation, Moscow
M. A. Lagarkova
Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine
Email: oslebedeva@rcpcm.org
Russian Federation, Moscow
References
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