Synergetic pathways for Parkinson’s disease therapy: The intersection of exercise and stem cell science

Abstract

Jiang et al reports a combined approach of exercise and induced pluripotent stem cell therapy in a Parkinson’s disease mouse model. The authors show that exercise can improve motor function by raising epinephrine levels and activating the Wnt1-Lmx1a pathway, thereby supporting dopaminergic differentiation. When paired with induced pluripotent stem cells, these effects are further enhanced, leading to greater behavioral improvements and molecular evidence of neuronal repair compared with either intervention alone. While the translational path from animal models to clinical application is far from straightforward - given variability in disease progression, the durability of grafted neurons, and safety concerns - the study highlights an important point: Progress may rely less on single “breakthroughs” and more on the thoughtful combination of diverse strategies. This integrative perspective could help shape future directions in Parkinson’s disease therapy.

Key Words: Parkinson’s disease; Induce pluripotent stem cells; Exercise; Dopaminergic differentiation; Neuronal repair

Core Tip: The most promising path forward for treating Parkinson’s disease may be through integrative therapies that synergistically combine regenerative medicine, such as stem cell transplants, with systemic interventions like exercise. This approach leverages exercise to prime the brain’s environment, thereby significantly enhancing the potential for cellular repair and urging a vital shift toward combined, interdisciplinary treatment strategies.

TO THE EDITOR

Parkinson’s disease (PD) is a serious condition in modern society with the increase of human life expectancy and environmental risk factors[1,2]. It remains undertreated worldwide, affecting more than six million individuals[3]. The relentless progression of the disease with deterioration of dopaminergic neurons limited the effects of the existing pharmacological and surgical therapies[4]. Induced pluripotent stem cell (iPSC) technology, first established by reprogramming somatic cells using the four Yamanaka factors, has revolutionized regenerative medicine[5-8]. Advances in this field have yielded safer and more efficient methods for generating iPSCs in both model organisms and humans[9], including the development of chemically iPSCs[9-13], which represents a future direction for obtaining safer (virus- and transgene-free) patient-specific cell sources for regenerative applications. Given their ability to model disease and enable personalized therapies, iPSCs hold significant promise for the treatments of neurodegenerative disorders such as PD[14,15].

In this issue of World Journal of Stem Cells, Jiang et al[16] reported a two-pronged strategy involving both behavioral and cellular approaches: Exercise combined with iPSC therapy. The authors demonstrate that exercise improves the neuronal repair-enhancing conditions at a molecular level, where epinephrine levels and a Wnt1-Lmx1a autoregulatory loop, which play key roles in the process of dopaminergic neurogenesis, are activated. When used in combination with iPSC transplantation, the effects are amplified and lead to significant improvement in locomotor behavior and increase in dopaminergic markers in Parkinsonian mice.

These findings led to the proposition that the therapeutic potential of stem cells, at least in some cases, may be enhanced by associating a concomitant physiological procedure, rather than by selecting one in prejudice to the other. Generally, the results support a growing direction in neurodegenerative research, that is, integrative interventions, including both systemic resilience and regenerative biology, are likely to be more effective than single-modality interventions.

Exercise, a well-known neuroprotective factor[17,18], can create a new neural microenvironmental niche as a molecular modifier to support cell-based interventions. Exercise-induced physiological changes (e.g., increased brain-derived neurotrophic factor, reduced neuroinflammation, improved cerebral blood flow) may provide a microenvironment more conducive to the survival, differentiation, integration, and functional maturation of transplanted iPSC-derived neurons. This raises a question how to design lifestyle interventions not as a supplementation to care, but as an active augmentation to regenerative medicine.

Interestingly, Jiang et al[16] also find the role of epinephrine, which increases during exercise and may activate the Wnt1-Lmx1a pathway. While intriguing, it remains unclear whether epinephrine effectively crosses the blood-brain barrier or whether its impact is primarily peripheral, indirectly influencing central signaling cascades. This question invites further mechanistic exploration of how systemic physiological cues modulate the local neural microenvironment.

Nevertheless, several critical challenges remain. Translating findings from mouse models to patients is rarely straightforward, particularly in PD, where onset, progression rate, and systemic responses can vary widely across individuals. Moreover, uncertainties persist regarding the long-term survival, functional integration, and stability of iPSC-derived neurons, as well as the safety risks associated with prolonged modulation of developmental signaling pathways. A further concern is the potential for residual pluripotent stem cells to form teratomas following transplantation. To mitigate these risks, future strategies may focus on the use of iPSC-derived neural stem cells, the lineage-restricted progenitors, which, compared to pluripotent iPSCs, have a significantly lower risk of uncontrolled proliferation and forming diverse tissues, such as teratomas[19].

These perspectives highlight that while recent experimental advances are promising, they represent only preliminary progress toward clinical application. The broader significance of Jiang et al’s findings[16] remains open to discussion, underscoring the need for cautious interpretation. Rather than treating interventions as isolated modalities - such as exercise for rehabilitation or stem cells for regeneration - it may be more productive to view them as complementary elements within a broader therapeutic framework. Moving forward, effective strategies for PD are likely to arise from interdisciplinary efforts that integrate molecular biology, clinical neuroscience, and rehabilitation science. To achieve this, new experimental and clinical tools will be required to address key questions, particularly how established and emerging therapies might be combined to provide the greatest benefit for patients.