Synergistic mesenchymal and neural stem cell therapy: Advancing neurorestoration in cerebral infarction

Abstract

Recent clinical and translational studies have increasingly highlighted the promise of combined stem cell strategies for neurorestoration following ischemic stroke. In this correspondence, we reflect on the recent trial by Yang et al, which reported that co-transplantation of mesenchymal stem cells (MSCs) and neural stem cells (NSCs) yielded significantly greater functional recovery in patients with acute cerebral infarction, as evidenced by improvements in both Barthel Index and National Institutes of Health Stroke Scale scores. Notably, this dual-cell intervention was accompanied by robust elevation of angiogenic and neurotrophic mediators, particularly vascular endothelial growth factor and basic fibroblast growth factor, suggesting a biologically plausible mechanism for the observed clinical benefit. MSCs contribute through trophic support, immunomodulatory effects, and promotion of vascular regeneration, whereas NSCs primarily facilitate neuronal replacement and reorganization of neural circuits. Together, these mechanisms offer a comprehensive, multitargeted approach to address the multifactorial nature of stroke pathology. Building on this pivotal work, we call for mechanistic studies and multicenter randomized clinical trials to refine cell dosing, timing, and bioengineering strategies, paving the way for the clinical integration of MSC/NSC co-therapy as a next-generation regenerative treatment for stroke.

Key Words: Mesenchymal stem cells; Neural stem cells; Co-transplantation; Cerebral infarction; Stroke recovery; Angiogenesis; Neurotrophic factors; Regenerative medicine; Neurorestoration; Cell therapy

Core Tip: The combination of mesenchymal stem cells and neural stem cells offers a biologically synergistic strategy for stroke repair. Mesenchymal stem cells release angiogenic and immunomodulatory factors - such as vascular endothelial growth factor and platelet-derived growth factor - that promote vascular regeneration and temper inflammation, while neural stem cells directly replace lost neural cells and stimulate neuroplasticity. Recent clinical evidence indicates that co-transplantation not only improves functional outcomes but also elevates vascular endothelial growth factor and basic fibroblast growth factor levels, suggesting enhanced vascular remodeling and neural circuit repair. This “cell-cocktail” concept may represent a transformative approach to addressing the multifactorial nature of cerebral infarction and advancing precision regenerative medicine.

TO THE EDITOR

We found the recent study by Yang et al[1] particularly compelling, as it represents the first investigation into the therapeutic potential of co-transplanting neural stem cells (NSCs) and mesenchymal stem cells (MSCs) in individuals with acute cerebral infarction. Their randomized clinical trial demonstrated that co-transplantation significantly enhanced functional recovery compared with standard care, as evidenced by improved Barthel Index scores and reduced National Institutes of Health Stroke Scale (NIHSS) ratings. Notably, this combinatorial approach was accompanied by substantial upregulation of angiogenic and neurotrophic mediators, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF)[1]. Nevertheless, this preliminary study was constrained by a limited sample size, a relatively brief follow-up period, and the absence of a sham control group, thereby necessitating a cautious interpretation of its findings.

These results are particularly compelling because they provide both clinical and mechanistic evidence supporting dual-cell therapy as a regenerative strategy for stroke. These observations align with the hypothesis that the elevated levels of VEGF and bFGF may play a role in promoting vascular and neural regeneration, thereby suggesting a potential mechanism underlying the observed clinical improvement. Furthermore, these findings are in concordance with prior reports indicating that MSC therapy alone can promote neurological recovery and enhance independence in activities of daily living[2]. The observed magnitude of NIHSS and Barthel Index improvements in this study underscores the clinical significance of the intervention, suggesting meaningful gains in motor performance and self-care ability consistent with a potent regenerative effect.

Mechanistically, the rationale for combining MSCs and NSCs in stroke therapy is compelling and biologically sound. MSCs secrete a diverse mix of trophic factors - that collectively stimulate angiogenesis, neurogenesis, and immune regulation[3,4]. In parallel, NSCs offer a unique capacity for cell replacement by differentiating into neurons, astrocytes, and oligodendrocytes, while simultaneously mitigating the hostile, pro-inflammatory microenvironment that develops after cerebral ischemia[5]. Experimental studies have consistently demonstrated that concurrent or sequential administration of MSCs and NSCs yields greater reductions in infarct volume and apoptotic cell death than treatment with either cell type alone[6].

In the clinical trial under discussion, the marked post-treatment increases in VEGF and bFGF levels are of particular importance. These molecules are well-recognized mediators of vascular and neural repair: VEGF promotes endothelial proliferation, capillary sprouting, and restoration of the blood-brain barrier, whereas bFGF (fibroblast growth factor 2) enhances neuronal survival, progenitor cell proliferation, and synaptic plasticity[6,7]. Their upregulation strongly suggests that the combined therapy augmented vascular remodeling and neural network reorganization. These biomarker changes align closely with the observed improvements in neurological outcomes, reinforcing the hypothesis that MSCs may “prime” the ischemic niche, thereby creating a supportive microenvironment for NSC engraftment and functional integration. Indeed, prior research has shown that MSC transplantation following stroke elevates VEGF and brain-derived neurotrophic factor expression and increases microvascular density within the peri-infarct region[3], while NSCs - especially those genetically modified to overexpress bFGF - exhibit improved survival and contribute to superior motor recovery[7]. The present clinical data effectively unify these mechanistic insights, illustrating how MSC/NSC co-transplantation reshapes the post-stroke milieu through trophic factor release, vascular support, and immune modulation[3,8].

From a translational perspective, this dual-cell approach addresses the inherently multifaceted nature of stroke pathology, which encompasses excitotoxicity, inflammation, blood-brain barrier disruption, and neuronal loss[8]. A single therapeutic agent rarely targets all these processes simultaneously. By integrating the immunomodulatory and stromal functions of MSCs with the neurogenic potential of NSCs, co-transplantation provides a multimodal intervention capable of tackling several injury pathways in parallel. Importantly, administration in the acute phase maximizes therapeutic leverage: MSCs act early to suppress inflammation and release reparative factors[3,5], effectively conditioning the microenvironment for subsequent NSC engraftment, differentiation, and circuit reconstruction. This “one-two punch” strategy is a well-established principle in regenerative medicine, and the present findings offer robust clinical validation of its efficacy in stroke.

Moreover, both autologous and allogeneic MSC preparations are already being tested in clinical stroke trials[2,8], and NSC transplantation has demonstrated safety in small-scale studies. Yang et al’s report[1] thus provides an essential proof-of-concept that combined cell therapy is both feasible and potentially superior to monotherapy. This work supports the emerging paradigm of “cell cocktails”, analogous to polypharmacology in drug development, with the potential to customize cell compositions according to patient-specific pathophysiology and timing of intervention.

Building on these encouraging findings, we concur with Yang et al[1] that future investigations should focus on both elucidating the biological underpinnings of MSC/NSC co-transplantation and expanding its clinical evaluation. The application of combined MSC and NSC therapy presents several practical challenges, including large-scale production and validation of two separate cell products, ensuring the safety of NSCs by mitigating potential tumorigenic risks, and determining optimal parameters for dosing, delivery methods, and timing within the co-transplantation protocol. Detailed mechanistic studies are needed to clarify how these two cell populations interact within the ischemic brain, including lineage-tracing of transplanted cells, characterization of immune and angiogenic signaling pathways, and systematic assessment of dosing and timing strategies. Advances in cell engineering - such as NSCs preconditioned with trophic factors or MSCs optimized for exosome production - could further potentiate therapeutic efficacy.

Equally important will be the design of large, multicenter randomized trials to confirm the clinical benefit and establish standardized treatment protocols. Such trials should incorporate widely accepted outcome measures, including NIHSS, modified Rankin Scale, and Barthel Index, alongside quantification of circulating and tissue biomarkers such as VEGF, fibroblast growth factor 2, and other neurotrophic mediators to correlate biological activity with functional recovery.

In conclusion, the work of Yang et al[1] provides promising indications that dual MSC/NSC transplantation represents a promising new frontier in regenerative stroke therapy. To our knowledge, this study constitutes the first clinical evaluation of combined NSC and MSC transplantation in the context of stroke, providing preliminary evidence supporting the practicality and therapeutic potential of this approach. These findings establish a foundation for the development of next-generation combinatorial cell therapies, which are expected to advance further with progress in bioengineering and the refinement of personalized treatment strategies.