Cell-based regenerative and rejuvenation strategies for treating neurodegenerative diseases

Abstract

Neurodegenerative diseases including Alzheimer's and Parkinson's disease are age-related disorders which severely impact quality of life and impose significant societal burdens. Cellular senescence is a critical factor in these disorders, contributing to their onset and progression by promoting permanent cell cycle arrest and reducing cellular function, affecting various types of cells in brain. Recent advancements in regenerative medicine have highlighted "R3" strategies-rejuvenation, regeneration, and replacement-as promising therapeutic approaches for neurodegeneration. This review aims to critically analyze the role of cellular senescence in neurodegenerative diseases and organizes therapeutic approaches within the R3 regenerative medicine paradigm. Specifically, we examine stem cell therapy, direct lineage reprogramming, and partial reprogramming in the context of R3, emphasizing how these interventions mitigate cellular senescence and counteracting aging-related neurodegeneration. Ultimately, this review seeks to provide insights into the complex interplay between cellular senescence and neurodegeneration while highlighting the promise of cell-based regenerative strategies to address these debilitating conditions.

Keywords: Cell-based therapy; Neurodegenerative diseases; Rejuvenation; Reprogramming; Senescence.

Fig. 1

Impact of cellular senescence and inflammation on neurodegeneration. This figure depicts the progression of neurodegenerative diseases driven by cellular senescence. Key processes include the activation of senescent markers (p65, p53, p16, p21) in astrocytes, which release senescence-associated secretory phenotype (SASP) factors (TNFα, iNOS, IL-1β, IL-6, IL-12, IL-23) that intensify neuroinflammation. Blood-brain barrier (BBB) breakdown leads to neutrophil and leukocyte infiltration, further contributing to inflammation. Microglia activation and the presence of senescent oligodendrocytes result in additional neuronal damage, characterized by Aβ plaque deposition, tau hyperphosphorylation, and myelin degradation, all of which are hallmarks of neurodegeneration

Fig. 2

Overview of cell-based strategies for treating neurodegenerative diseases. This diagram summarizes cell-based strategies to treat neurodegenerative diseases. Stem cells, including pluripotent stem cells (PSCs), mesenchymal stem cells (MSCs), and NSCs, may rejuvenate existing cells and regenerate or replace damaged ones by serving as sources for generating neural cell types like neurons, astrocytes, and oligodendrocytes. Non-neuronal cells can also be directly reprogrammed into neurons, bypassing the stem cell stage. Additionally, aged neural cells undergo transient reprogramming to a stem-like state, promoting rejuvenation and potentially reversing age-related damage. These methods aim to produce functional neural cells that could replace or repair damaged cells in neurodegenerative conditions, helping to restore brain function and slow disease progression

Fig. 3

Potential mechanisms underlying the stem cell therapies. This schematic illustrates how stem cell–based therapies combat neurodegeneration through multiple mechanisms in one integrated approach. Newly grafted or converted neural cells (center) replace or supplement degenerating neurons (upper left), while transplanted stem cells or induced cells also bolster neurogenesis (upper right) by differentiating into neurons, astrocytes, oligodendrocytes, or interneurons. Moreover, these cells secrete neurotrophic factors (left) that enhance cell survival and plasticity, and release anti-inflammatory mediators (lower left) to modulate immune responses involving peripheral macrophages, microglia, and astrocytes. Finally, healthy mitochondria can be transferred to damaged neurons (lower right), improving energy production and reducing oxidative stress