Emerging regenerative medicine and tissue engineering strategies for Parkinson’s disease

Abstract

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease, affecting 1–2% of people over 65. The classic motor symptoms of PD result from selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in a loss of their long axonal projections to the striatum. Current treatment strategies such as dopamine replacement and deep brain stimulation (DBS) can only minimize the symptoms of nigrostriatal degeneration, not directly replace the lost pathway. Regenerative medicine-based solutions are being aggressively pursued with the goal of restoring dopamine levels in the striatum, with several emerging techniques attempting to reconstruct the entire nigrostriatal pathway—a key goal to recreate feedback pathways to ensure proper dopamine regulation. Although many pharmacological, genetic, and optogenetic treatments are being developed, this article focuses on the evolution of transplant therapies for the treatment of PD, including fetal grafts, cell-based implants, and more recent tissue-engineered constructs. Attention is given to cell/tissue sources, efficacy to date, and future challenges that must be overcome to enable robust translation into clinical use. Emerging regenerative medicine therapies are being developed using neurons derived from autologous stem cells, enabling the construction of patient-specific constructs tailored to their particular extent of degeneration. In the upcoming era of restorative neurosurgery, such constructs may directly replace SNpc neurons, restore axon-based dopaminergic inputs to the striatum, and ameliorate motor deficits. These solutions may provide a transformative and scalable solution to permanently replace lost neuroanatomy and improve the lives of millions of people afflicted by PD.

TNFα increases tyrosine hydroxylase expression in human monocytes

“…The lack of a robust and sensitive assay to measure low levels of TH protein has hampered the field's ability to investigate TH protein levels in peripheral immune cells in diseases characterized by altered catecholamine tone. For example, in PD, due to its spatially restricted expression, decreases in TH levels in the basal ganglia are readily detectable 27,28 , whereas changes in TH levels in other brain regions (i.e., amygdala, hippocampus, cortical regions) are reported in the later stages of PD 29,30 . In contrast, very low TH levels in countless immune cells spread across the body have made it difficult to study TH protein levels in peripheral immune cells.…”

Pluripotent Stem Cell Therapies for Parkinson Disease: Present Challenges and Future Opportunities

“…Typically, 200,000–420,000 dopamine neurons reside in human midbrain, and it is estimated that 50% loss of those DA neurons leads to the PD symptom ( Brichta and Greengard, 2014 ). According to preclinical studies using fetal tissue or hPSC-derived mDA cell, 1200–2400 surviving TH + neurons in rat, 13,000 in primate, 40,000–80,000 in the human brain may be required to achieve a meaningful therapeutic effect ( Hallett et al, 2015 ; Harris et al, 2020 ). The current bottleneck in delivering cells to the brain is that typically less than 10% of grafted mDA neurons survive following transplantation ( Brundin et al, 2000 ; Thompson and Bjorklund, 2012 ; Hallett et al, 2014 ).…”

Biofabrication of natural hydrogels for cardiac, neural, and bone Tissue engineering Applications

“…Tissue engineering, as defined by Langer and Vacanti in 1993, is an interdisciplinary field that applies both the principles of life sciences and engineering to develop biological substitutes or entire organs [ 1 ]. Beyond that initial goal, tissue-engineered constructs have found a variety of new applications, such as being research tools that could improve our understanding and testing of diseases [ [2] , [3] , [4] , [5] , [6] ]. Furthermore, the development of personalized therapies is expected to be further facilitated by utilizing patient-specific cells and biological factors [ [7] , [8] , [9] , [10] ].…”