Exercise with induced pluripotent stem cells enhances Wnt1-Lmx1a signaling and dopaminergic neurogenesis to alleviate Parkinsonian symptoms

Abstract

This article focused on the recent contribution by Jiang et al, who demonstrated that voluntary exercise can significantly potentiate the effects of induced pluripotent stem cell transplantation in a Parkinson’s disease (PD) model through activation of the Wnt1-Lmx1a signaling cascade. Jiang et al’s findings highlight the role of exercise as a molecular modulator of neurogenesis and support the development of integrated strategies combining physical activity, stem cell transplantation, and biomaterials to improve outcomes in PD. We highlight exercise as a molecular modulator that fosters a neurogenic milieu, recommend examining additional developmental signals (sonic hedgehog, fibroblast growth factor 8, bone morphogenetic protein), and suggest biomaterial-based strategies to support graft survival and integration. We also stress the need to optimize exercise regimens in relation to transplantation, framing these insights within a translational strategy for advancing regenerative therapies in PD.

Key Words: Parkinson’s disease; Induced pluripotent stem cells; Exercise; Wnt1-Lmx1a signaling; Dopaminergic neurogenesis; Biomaterials; Neuroregeneration; Stem cell transplantation

Core Tip: This letter builds on Jiang et al’s recent findings that voluntary exercise enhances the therapeutic impact of induced pluripotent stem cell transplantation in Parkinson’s disease by activating the Wnt1-Lmx1a pathway. We highlight exercise as a molecular modulator that fosters a neurogenic milieu, recommend examining additional developmental signals (sonic hedgehog, fibroblast growth factor 8, bone morphogenetic protein), and suggest biomaterial-based strategies to support graft survival and integration. We also stress the need to optimize exercise regimens in relation to transplantation, framing these insights within a translational strategy for advancing regenerative therapies in Parkinson’s disease.

TO THE EDITOR

We read with great interest the recent contribution by Jiang et al[1], who demonstrated that voluntary exercise can significantly potentiate the effects of induced pluripotent stem cell (iPSC) transplantation in a Parkinson’s disease (PD) model through activation of the Wnt1-Lmx1a signaling cascade. Their observation that physical activity alone elevates systemic adrenaline and Wnt1 expression, while its combination with iPSC grafts robustly promotes dopaminergic (DA) differentiation, provides strong evidence of the therapeutic synergy between rehabilitation strategies and cell-based interventions[1]. We concur with the authors’ conclusions and would underscore that exercise generates a pro-neurogenic microenvironment that not only supports graft survival and neuronal differentiation but also facilitates integration of transplanted cells within host neural circuits[2]. Future studies may extend these findings by investigating additional developmental regulators of DA fate such as sonic hedgehog (SHH), fibroblast growth factor 8 (FGF8), and bone morphogenetic protein (BMP)[3,4]. Attention should also be given to optimizing the timing, intensity, and duration of exercise relative to grafting, as therapeutic outcomes are highly dependent on intervention windows[2]. Furthermore, the incorporation of bioengineered scaffolds or nanomaterial-based systems that replicate the neural niche and provide localized trophic support could further enhance graft survival and functional recovery[3]. Collectively, Jiang et al’s findings[1] highlight the role of exercise as a molecular modulator of neurogenesis and support the development of integrated strategies combining physical activity, stem cell transplantation, and biomaterials to improve outcomes in PD[2].

Synergistic effects of exercise and iPSC therapy

The researchers report that treadmill exercise in PD mice not only alleviates motor impairments but also biochemically primes the midbrain toward DA neurogenesis. Physical activity elevated systemic catecholamines and upregulated local Wnt1 expression, thereby activating Wnt/β-catenin signaling and Lmx1a induction. Following transplantation of iPSC-derived neural progenitors, this environment established a reinforcing Wnt1-Lmx1a loop that directed cells toward a tyrosine hydroxylase-positive DA phenotype, significantly enhancing functional recovery[1]. These findings align with prior evidence that environmental stimulation, including exercise, generates a supportive microenvironment for graft survival and integration. Experimental models of enriched environments and exercise have demonstrated two complementary mechanisms: First, exercise-induced factors such as neurotrophins, angiogenic mediators, and chemokines promote survival, proliferation, and differentiation of transplanted cells; second, physical activity functionally conditions grafted cells, enabling them to adapt to host neural signals and form synaptic connections. In this way, exercise benefits both the host tissue and the graft[2]. For instance, Moriarty et al[5] in 2025 recently reported that voluntary wheel running markedly promoted the synaptic plasticity and functional incorporation of transplanted human pluripotent stem cell-derived DA neurons in a rodent model of PD, thereby expediting motor function restoration. Importantly, exercise alone improved both motor and non-motor parameters in Jiang et al’s PD model[1], reflecting its ability to stimulate endogenous neuroplasticity. Lifestyle factors such as regular physical activity are well known to influence neurodegenerative trajectories: Sedentary behavior accelerates disease onset, whereas exercise upregulates protective molecules such as brain-derived neurotrophic factor (BDNF) and vascular growth factors, supporting neuronal resilience[6]. Thus, Jiang et al’s conclusion[1] - that exercise potentiates iPSC-based therapy via Wnt1-Lmx1a activation - extends previous observations and reinforces the principle that rehabilitation and cell replacement therapies act in concert to rebuild neural circuits in PD[2].

Additional neurogenic pathways and biomaterial-based approaches

An important extension of Jiang et al’s findings[1] is the need to investigate other developmental signaling cascades that regulate midbrain DA specification in the context of exercise combined with iPSC therapy. In vivo, DA neuron fate is orchestrated by dual-SMAD inhibition together with graded morphogen signals: High levels of SHH and FGF8 define ventral midbrain identity, whereas suppression of BMP activity permits neural commitment[3,4]. Cooper and colleagues further demonstrated that efficient in vitro differentiation of human embryonic stem cells/iPSCs into midbrain DA neurons requires a potent form of SHH, FGF8α, and retinoic acid for precise regionalization[4]. Although these pathways were not addressed by Jiang et al[1], their centrality suggests that future studies should examine whether exercise influences SHH, FGF, or BMP signaling in both grafted and host cells. For example, exercise may enhance SHH release from glial or neuronal sources or modulate FGF gradients, thereby working in synergy with Wnt signaling to promote DA fate. Likewise, exercise-driven suppression of astroglial BMP activity could further facilitate neurogenesis. As data directly linking physical activity to these developmental regulators remain limited, systematic investigation is warranted.

The efficient in vitro differentiation of pluripotent stem cells into midbrain DA neurons depends on the integration of multiple signaling cues. Common induction protocols incorporate compounds such as CHIR99021, a glycogen synthase kinase 3 beta inhibitor that enhances Wnt pathway activation, and Forskolin, which elevates intracellular cAMP levels, alongside exogenous neurotrophic factors like BDNF and glial cell line-derived neurotrophic factor (GDNF) that recapitulate key elements of the embryonic midbrain microenvironment. Future research should investigate whether physiological stimuli such as exercise or bioengineered scaffolds can similarly modulate these developmental signaling cascades in vivo or serve as functional analogues - for instance, through localized BDNF release - to promote more robust differentiation and maturation of transplanted neural grafts[2-4].

Another promising avenue involves biomaterial-based strategies to optimize graft survival and integration. Biocompatible scaffolds and nanomaterials can replicate essential features of the neural stem-cell niche. Injectable hydrogels or aligned nanofiber matrices enriched with extracellular matrix proteins recreate aspects of midbrain architecture, supporting neuronal adhesion and axonal growth. Integrating such scaffolds with exercise could yield dual benefits: Scaffolds provide localized trophic and structural support, while exercise amplifies systemic neurotrophic and vascular responses[1]. It was emphasized that the capacity of nanomaterial scaffolds to “simulate the in vivo microenvironment” and drive neural stem cell differentiation. In parallel, engineered nanoparticles conjugated with neurotrophic factors (e.g., GDNF, BDNF) or Wnt agonists can be pre-associated with transplanted cells, enabling localized, sustained release of instructive cues. Such “smart” delivery systems have already demonstrated improved graft survival and functional integration in preclinical PD models[3]. Collectively, these strategies highlight the potential of biomaterials to augment the exercise-iPSC synergy by maintaining continuous molecular support and facilitating precise graft-host communication. Critically, biomaterial scaffolds intended for neural applications must adhere to rigorous biocompatibility standards. They should be non-toxic, non-immunogenic, and possess mechanical and chemical characteristics that closely resemble native brain tissue - such as appropriate softness and biodegradability - to minimize the risk of gliosis, scarring, or chronic inflammatory responses.

Advanced or “smart” scaffolds are frequently engineered to serve as localized delivery systems, capable of releasing neurotrophic factors or therapeutic agents in a spatially and temporally controlled manner. As an illustration, Wang et al’s graphene-based nanoelectrode construct demonstrated safe co-migration with transplanted neural cells while delivering precise electrical stimulation, exemplifying how multifunctional materials can combine trophic support with neuromodulatory capabilities without compromising biocompatibility[7]. Key design parameters - including degradation kinetics, conductive surface coatings, and targeting ligand functionalization - are essential to ensure that such implantable platforms actively facilitate neural repair rather than provoke adverse tissue reactions. Innovative neuromodulation strategies are showing considerable potential[7,8]. For example, the same group developed wireless graphene-based nanoelectrodes capable of interfacing with transplanted neural stem cells to deliver precise electrical stimulation[7]. This targeted stimulation markedly enhanced neural stem cell differentiation into DA neurons (rising from approximately 6% to nearly 38%) and led to significant improvements in motor function in PD mouse models[7]. These findings highlight how electrical modulation can actively drive neural differentiation and could be synergistically integrated with physical rehabilitation and biomaterial scaffolds for enhanced therapeutic outcomes. Finally, careful calibration of rehabilitation parameters is essential. The timing, intensity, and duration of exercise relative to transplantation likely play decisive roles in determining efficacy. Evidence from stroke models indicates that overly intense early exercise may compromise graft outcomes, while delayed, moderate rehabilitation is more favorable[2].

From a clinical standpoint, exercise recommendations for PD typically align with established professional guidelines. For instance, the Parkinson’s Foundation and the American College of Sports Medicine suggest engaging in approximately 150 minutes per week of moderate-to-vigorous aerobic activity (such as 30 minutes on three separate days), complemented by resistance and balance training two to three times per week. These structured programs emphasize supervised exercise sessions performed while patients are in their optimal medication state. Nonetheless, standardized exercise regimens tailored to the timing of cell transplantation or neural graft integration have yet to be defined, highlighting an important avenue for future clinical investigation[9].

In PD, defining the optimal initiation window is equally important: Premature exercise could aggravate inflammatory responses in the graft microenvironment, whereas postponing activity may allow engraftment to stabilize before stimulation. Dose-response studies comparing voluntary vs forced exercise, short vs extended regimens, and different intensities would provide valuable insights into maximizing neurogenic signaling while avoiding stress. At the same time, fine-tuning the quantity and developmental stage of transplanted iPSC-derived cells, alongside modulation of Wnt1 activation, may help identify synergistic conditions that optimize clinical translation.

Exercise as a molecular driver of neurogenesis

Evidence from the investigators’ study and earlier studies underscores exercise as a powerful molecular regulator of brain repair. Physical activity promotes the release of multiple growth factors - including BDNF, GDNF, and vascular endothelial growth factor - alongside chemokines and neurotransmitters, together generating a favorable microenvironment for neurogenesis[1,2]. In the PD model, Jiang et al[1] demonstrated that exercise specifically elevates adrenaline and Wnt1 levels, which subsequently enhance Lmx1a expression and DA differentiation markers. These findings suggest that exercise-mediated neurogenesis operates partly through canonical Wnt signaling, extending beyond its effects on Lmx1a alone. Importantly, exercise by itself improved motor performance, providing direct evidence of its capacity to remodel host circuitry. Functionally, exercise acts on both sides of the repair process: It conditions the host milieu by altering chemical and electrical cues, while simultaneously shaping transplanted cells to adopt appropriate functional characteristics[2]. This dual modulation provides a strong rationale for combining structured rehabilitation with cell therapy as an integrated approach to neurodegenerative disease.

Conclusions and future directions

Jiang et al[1] convincingly show that treadmill exercise, a straightforward rehabilitation intervention, amplifies the therapeutic efficacy of iPSC-derived cell therapy through activation of the Wnt1-Lmx1a loop. This represents just one facet of the broader regenerative potential of exercise.

Some important limitations can be identified in the study by Jiang et al[1]. The experimental design included only ten mice per group, representing a relatively small cohort that may reduce statistical robustness and limit the generalizability of the findings. Additionally, the use of forced treadmill exercise rather than voluntary activity could have induced stress, thereby confounding neurobiological interpretations. The systemic administration of iPSCs via tail-vein injection further raises questions regarding the precision of cellular homing to the midbrain, as well as the long-term survival and integration of transplanted cells. Behavioral assessments were primarily confined to motor coordination testing using the rotarod assay, which, while informative, does not encompass key Parkinsonian features such as bradykinesia or non-motor deficits. Moreover, the observed molecular changes - namely elevated Wnt1 and Lmx1a expression - suggest potential engagement of DA differentiation pathways but do not conclusively demonstrate the formation of functionally integrated DA neurons or durable neural repair. Finally, the hypothesized mechanism involving adrenaline-mediated activation of Wnt/β-catenin signaling remains largely speculative, as no direct evidence supports exosome-based transport, and alternative mechanisms - such as modulation of inflammatory responses or mitochondrial activity - were not systematically excluded. Collectively, these limitations underscore the need for further mechanistic and translational validation.

Moving forward, further attention should be directed toward other developmental signals such as SHH, FGF8, and BMP, which are central to DA neuron specification, to assess whether exercise modulates these pathways[3,4]. At the same time, refining exercise “dosing” in relation to grafting, and incorporating supportive bioengineering technologies - including scaffolds and controlled growth-factor delivery - could substantially improve graft survival and integration[3]. Ultimately, a combinatorial paradigm that unites cell transplantation, exercise-based rehabilitation, and microenvironmental engineering holds promise for restoring nigrostriatal function.

Looking forward, the convergence of these approaches outlines a promising trajectory toward clinical translation. Future studies should focus on confirming both safety and therapeutic efficacy in larger preclinical models, followed by phase I clinical trials that combine structured exercise programs with stem cell transplantation. The incorporation of advanced biomaterials, such as controlled-release scaffolds, will be pivotal for the localized delivery of growth factors and the long-term maintenance of graft viability in vivo. While regulatory, scalability, and manufacturing hurdles remain significant, the encouraging outcomes from preclinical research suggest that a multimodal therapeutic paradigm - integrating cell replacement, exercise-based rehabilitation, and engineered microenvironments - could ultimately lead to substantial functional benefits for individuals living with PD[7,8]. We commend Jiang et al[1] for illuminating exercise as a molecular partner to stem cell therapy and anticipate that future work, within World Journal of Stem Cells and beyond, will continue advancing these insights toward effective clinical translation in PD.