Cell Replacement to Reverse Brain Aging: Challenges, Pitfalls, and Opportunities

Abstract

Current antiaging strategies focusing on druggable targets have met with relatively limited success to date. Replacement of cells, tissues, and organs could provide an alternative means for targeting age-induced damage and potentially eliminating some of it. However, before this is a viable option, numerous challenges need to be addressed. Most notably, whether the brain, which defines our self-identity, is amenable to replacement therapies is unclear. Here, we consider whether progressive cell replacement is a potential approach to reverse brain aging without grossly altering function. We focus mainly on the neocortex, seat of our highest cognitive functions, because of abundant knowledge on neocortical development, plasticity, and how the neocortex can functionally incorporate new neurons. We outline the primary challenges for brain cell replacement, and key areas that require further investigation.

Adult Neurogenesis and the Promise of Adult Neural Stem Cells

“…An understanding of the scope of cell-replacement as a potential therapy beyond adult NSC can be found in a recent review. 86…”

“…An understanding of the scope of cellreplacement as a potential therapy beyond adult NSC can be found in a recent review. 86 Another important factor to consider in the neurodegenerative context, would be the niche signals. A neurodegenerative microenvironment will be substantially different from the steady-state niche of adult neurogenesis.…”

Review: Synthetic scaffolds to control the biochemical, mechanical, and geometrical environment of stem cell-derived brain organoids

“…They found that the resulting organoids recapitulated different AD-pathologies including amyloid aggregation, hyper-phosphorylation of Tau, and endosome abnormalities. Similarly, brain organoid technology can be used to generate patient's-specific tissue that can be used for regeneration and reconstitution after insults such as tumor biopsies, neurodegenerative diseases, and neurological trauma (Hebert and Vijg, 2018 and Ludwig et al , 2018).…”

3D-printed microplate inserts for long term high-resolution imaging of live brain organoids

“…For example, this technology has revealed how impairment of neural progenitor cells (NPCs) found in Zika virus infection at various stages of human embryogenesis contribute to microcephaly [ 11 ] as well as used to recapitulate different Alzheimer’s Disease pathologies, such as amyloid aggregation, Tau hyper-phosphorylation and endosome abnormalities [ 23 ]. Patient-derived brain organoids could also be used to produce patient-specific tissue for tissue regeneration after insults such as tumour biopsies, neurodegenerative disease and neurological trauma [ 24 , 25 ].…”