Letter to the Editor: Exercise and induced pluripotent stem cells for Parkinson’s disease

Abstract

In this letter, we comment on the study by Jiang et al published in the recent issue of the World Journal of Stem Cells, which explores a combined therapeutic approach of exercise with induced pluripotent stem cells (iPSCs) for Parkinson’s disease (PD) using a mouse model. Currently, PD is primarily treated symptomatically as there are no treatment options available to prevent or cure it. While previous studies have examined exercise and iPSCs individually for PD, there is limited research on using them concurrently. Jiang et al aimed to evaluate this combined treatment method and investigate the underlying mechanisms. The results of this study indicate a synergistic relationship between exercise and iPSCs, demonstrating improved motor symptoms, and notably, elevated levels of proteins thought to be significant factors in the differentiation of dopaminergic neurons. This emphasizes that more research is needed to critically evaluate the underlying mechanisms of PD and neuronal differentiation in the hopes of developing effective and sustainable treatment options.

Key Words: Parkinson’s disease; Pluripotent stem cells; Neurodegeneration; Dopaminergic neurons; Wnt1; Lmx1a; Exercise

Core Tip: This letter to the editor discusses the recent study by Jiang et al on induced pluripotent stem cells and exercise for Parkinson’s disease. Treatment with induced pluripotent stem cells provides a promising option for Parkinson’s disease patients by replacing lost dopaminergic neurons, while exercise alone has been shown to improve outcomes in these patients. A combination of these therapies has shown a potentially synergistic effect by activating the Wnt1-Lmx1a loop in a mouse model.

TO THE EDITOR

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that increases in prevalence with age[1]. The pathological mechanism behind PD is thought to be caused by a degeneration of dopaminergic (DA) neurons within the substantia nigra of the brain, with current pharmacologic and surgical interventions acting at this mechanism[2,3]. Research on exercise and induced pluripotent stem cells (iPSCs) for Parkinson’s has shown these are both potentially beneficial treatment options, but combined treatment has not been thoroughly studied[4,5]. In this article, we will discuss the findings of Jiang et al[6], who demonstrated that combined therapy of exercise and iPSCs in a Parkinson’s mouse model produces a beneficial synergistic effect.

Mechanisms of combined exercise and iPSC therapy

We read with great interest the study by Jiang et al[6] published in the recent issue of the World Journal of Stem Cells, which explored not only the potential benefits of a combined therapeutic approach of exercise and iPSCs in PD, but also the associated mechanisms. Previous research has shown the signaling pathways involved in neuronal differentiation into DA neurons, including the Wnt1-Lmx1a and Shh-Foxa2 regulatory loops[7]. Jiang et al[6] further explored this connection by using a PD mouse model to evaluate exercise and iPSCs for treatment. The study included four groups: A sedentary group, an exercise-only group, an iPSC-only group, and the combined exercise and iPSC treatment group. Motor outcomes were measured using the rotarod and open-field test. Comparing the exercise-only to the iPSC-only group showed a statistically significant improvement in motor ability (P < 0.01) as well as gene expression level of Wnt1 (P < 0.05) in the exercise-only group. The combined exercise and iPSC treatment group showed statistically significant (P < 0.05) increased gene expression levels of Wnt1, Lmx1a, and Neurog2. These findings indicate that activation of the Wnt1-Lmx1a loop through exercise allowed more effective differentiation of the stem cells into DA neurons, producing a more effective treatment of PD symptoms.

Limitations

There are several limitations of the study by Jiang et al[6] that should be noted. Firstly, the motor measures used were restricted to open-field and rotarod. Other established measures of motor coordination in mice such as beam walking, or footprint analysis for gait[8], would increase the validity of their results. Secondly, their mouse model of PD is limited as it relies on the neurotoxin-induced death of DA neurons, without the intracellular aggregates of α-synuclein characteristic of PD[2]. Thus, it remains unclear whether their results and studied mechanisms would translate effectively to a human with PD. Thirdly, as pointed out by the authors, they were unable to definitively trace the differentiation of the iPSCs into DA neurons, and relied on the expression of OCT4, TH, Wnt1, Lmx1a, and Neurog2 as evidence. As OCT4 is a marker for undifferentiated stem cells[5], and without definitive tracing of iPSC differentiation, the other markers listed do not provide sufficient evidence to conclude that the iPSCs successfully differentiated into DA neurons. Lastly, the mechanism connecting exercise and activation of Wnt1 was not fully explored. They found that exercise-only and combined exercise and iPSC groups both demonstrated increased epinephrine levels, and suggested that could activate the Wnt1 signaling pathway through β-adrenergic receptors. However, the authors noted that they did not directly investigate this relationship, and future research should explore this mechanism further.

Clinical implications

Currently, there are several clinical trials using stem cell treatments for PD that are in their early phases[5]. The study by Jiang et al[6] emphasizes the potential of exercise and iPSCs as treatment options for PD patients and reinforces the trend for future research on stem cell therapies. While this study was conducted using mouse models, it still provides a promising future for PD treatment[6]. Regarding practical applications, exercise may be an accessible treatment option for patients, while stem cells come with associated difficulties, including patient accessibility and personal moral dilemmas related to cell sourcing, such as those derived from human embryos[9]. While iPSCs specifically are derived from adult cells, ethical issues regarding procurement and genetic modifications must still be considered and addressed by adhering to ethical guidelines such as those set forth by the International Society for Stem Cell Research[10].

Conclusion

In conclusion, a combined therapy of exercise in conjunction with iPSCs represents a hopeful treatment option for PD patients. Further exploration of relationships in neuronal differentiation is needed to completely understand these mechanisms and develop effective PD treatments. Stem cells, in combination with exercise or other therapies, have the potential to become an important treatment option for PD and other neurodegenerative diseases.