Synergistic potential of combined neural stem cells and mesenchymal stem cells therapy in acute cerebral infarction: A perspective

Abstract

Acute cerebral infarction (ACI) is one of the leading causes of mortality and long-term disability in adults, often resulting in neuronal loss and necrosis, accompanied by severe neurological deficits. Neural stem cells and mesenchymal stem cells play crucial roles in neural repair and protection, primarily through promoting angiogenesis, reconstructing neural networks, and inhibiting neuronal apoptosis. A recent randomized controlled trial demonstrated that combined neural stem cell and mesenchymal stem cell therapy significantly enhances neurological recovery in ACI patients by upregulating the expression of vascular endothelial growth factor and basic fibroblast growth factor. This study provides a theoretical foundation and clinical support for the application of stem cell-based precision medicine in ACI. This letter shares our perspectives on the combined stem cell therapy for ACI.

Key Words: Mesenchymal stem cells; Neural stem cells; Acute cerebral infarction; Growth factors; Cell transplantation

Core Tip: We note a recently published randomized controlled trial investigating the efficacy and mechanisms of combined mesenchymal and neural stem cell therapy for acute cerebral infarction. The study systematically validated, at the clinical level, the therapy’s role in promoting neurological recovery through the regulation of vascular endothelial growth factor and basic fibroblast growth factor, while demonstrating a favorable safety profile. In this letter, we share our perspectives.

TO THE EDITOR

We have closely examined the randomized controlled trial by Yang et al[1], which explored the potential therapeutic value of combined mesenchymal stem cell (MSC) and neural stem cell (NSC) therapy for acute cerebral infarction (ACI). This work offers valuable insights into the promising field of regenerative medicine and holds important implications for the clinical management of ischemic stroke. While the results are compelling, several aspects warrant further discussion.

A growing body of evidence suggests that stem cell-based therapies hold promising potential for the treatment of ACI. Studies have revealed that the mechanisms by which NSCs promote neural repair in the brain can be categorized into the following aspects: Paracrine effects; promotion of angiogenesis and restoration of vascular integrity; modulation of inflammatory responses; neuroprotection; and cell replacement[2]. The synergistic actions of these mechanisms position NSCs as a highly promising cellular therapy for cerebral infarction. Meanwhile, MSCs have garnered significant attention due to their multipotent mechanisms, which facilitate repair through neural differentiation, promotion of angiogenesis, anti-apoptotic effects, and immunomodulation[3]. For instance, intravenous administration of umbilical cord-derived MSCs in rodents has been demonstrated to mitigate pathological damage, reduce inflammatory infiltration, and enhance chemokine expression, thereby promoting neural repair and regeneration[4].

However, monotherapy with a single cell type still faces challenges. Although NSCs possess the unique potential to differentiate into neurons and glial cells, directly replacing damaged neural tissue, their low survival and integration rates within the hostile post-ischemic microenvironment significantly limit their therapeutic efficacy[5]. This study used combined NSC and MSC therapy to treat ACI patients, and it reveals that this therapy boosts the expression of vascular endothelial growth factor and basic fibroblast growth factor, pointing to a potential synergistic effect. However, it’s still unclear if this increased expression reflects true synergy or just an additive effect. Future studies that include a single transplantation group could help further clarify the link between stem cell therapy and vascular endothelial growth factor/basic fibroblast growth factor.

Second, this study adopted a treatment approach using sequential injection of NSCs followed by MSCs, which provides valuable reference for the clinical application of stem cell therapy. However, we also note that Hosseini et al[6] adopted an “MSC-first, NSC-second” approach, and also observed positive therapeutic outcomes. Furthermore, some in vitro experiments suggest that the presence of MSCs may influence NSC differentiation and simultaneously promote their proliferation and survival rates[7]. Therefore, future studies that compare the therapeutic effects of different administration sequences may help expedite the clinical translation of stem cell therapies.

Third, this study started stem cell therapy in the acute phase (within 7 days), which raises important questions about the optimal time window for stem cell treatment in ACI. A meta-analysis of NSC therapy for ACI indicates that the 24-72 hours window post-stroke may be the optimal treatment window for NSCs[8]. Meanwhile, another animal study administered human umbilical cord-derived MSCs on days 4, 7, and 14 following middle cerebral artery occlusion, and found superior efficacy when given on days 4 and 7[4]. Recent animal studies also show that neural progenitor cells transplanted on day 7 have higher survival rates than those transplanted on day 1 after cortical infarction[9]. Since treatment timing plays a critical role in efficacy and the optimal window remains unclear, we suggest including intervention groups at different time points in future research. Paired with multimodal imaging and biomarker evaluations, this approach will offer clearer understanding of how different treatment windows affect ACI outcomes.

Fourth, future studies should consider incorporating stratified analysis by cerebral infarction etiology or refining inclusion criteria. Different cerebral infarction subtypes have a significant impact on prognosis and treatment outcomes, and distinguishing among these subtypes could help clarify whether the benefits of combined therapy differ based on the underlying stroke mechanism. Additionally, the lack of blinding could introduce potential bias. While blinding is challenging in patients undergoing surgical interventions, integrating it into future studies would strengthen the reliability of findings. Furthermore, combining MSC and NSC therapy may theoretically increase tumorigenic risk, so implementing longer follow-up periods in future studies would allow for a more comprehensive assessment of this treatment’s long-term safety profile.

In brief, Yang et al’s work[1] marks a significant advance in combining stem cell therapies for ischemic stroke, and it undoubtedly contributes meaningfully to the field of regenerative medicine. However, certain limitations of the study - including the lack of long-term safety data, limited extrapolation potential, and cost-related considerations - could limit its widespread clinical adoption in the near term. Future multicenter studies that incorporate longer follow-up periods, larger sample sizes, diverse stroke subtypes, and distinct stem cell treatment groups are poised to help further refine clinical application strategies for stem cell therapy.