Introducing my latest blog commentary published in the esteemed journal Stroke! As I shared that blog on social media, it captured the attention of my mentor, Prof. Heng Zhao, who graciously offered insightful comments. Our conversation delves into the study's nuances, intriguing findings, and potential future directions. Join us in this illuminating exploration as we engage in a captivating conversation. – Hansen

Prof. Heng Zhao’s Comment: 
What are your thoughts on the major limitations of this study? If HMGB1 treatment did not affect OL migration, it might have rendered the in vitro study less meaningful. Additionally, are you aware if the authors further investigated how HMGB1 inhibition affects OL migration?

Regarding an interesting point about TLR2, do you happen to know why they specifically chose TLR2? Does TLR4 also express in OL?

Your comment is very clear in summarizing the major findings of this study. It is impressive how you highlighted the ERK cell signaling pathway's role in regulating F-actin activity - your summary is superb. I would like to suggest offering additional comments about the study's potential pitfalls and future research directions. Your insights could further enrich the discussion and contribute to the scientific rigor of the research.

My response:

Dear Prof. Zhao,

Thank you for your valuable feedback on my blog post! I completely agree that this study has several limitations that warrant further investigation to strengthen its conclusions.

Regarding the mechanistic aspect, more evidence is needed to demonstrate the role of HMGB1 in OPC migration in vivo. Examining the cellular source of HMGB1 release and the gradience of HMGB1 release from the ischemic core to the peri-infarct region could provide further insights. Additionally, conducting in vivo experiments with HMGB1 inhibition could provide further evidence to establish its critical role in OPC migration.

Regarding the choice of TLR2 over TLR4, I share your curiosity about why the authors focused on TLR2 and did not investigate TLR4, although they ruled out the role of RAGE in vitro. While it seems that TLR4 is not expressed in OLs, there is uncertainty about TLR4 expression in OPCs. In a previous study, I observed a more significant change in brain TLR2 expression after MCAO stroke compared to TLR4 expression. However, even if Ols/OPCs do not express TLR4, this does not necessarily exclude the possibility of TLR4 playing a role in OPC migration in conditions involving multiple cell types and complex communication.

TLR2-/- mice used in the study are general knockout and not cell type-specific. Consequently, in the in vivo study, the researchers have not definitively determined whether TLR2 on OPCs is critical or if TLR2 expression on other cell types plays a crucial role. However, the in vitro experiments provided valuable insights, showing that microglia-mediated OPC migration was independent of TLR2/HMGB1 signaling. This finding led the authors to speculate that TLR2 on OPCs/Ols may indeed play an important role in their migration.

The ERK1/2-FAK signaling and F-actin polymerization findings are indeed intriguing. However, it is essential to recognize that TLR2/HMGB1 signaling might induce the production of growth factors and cytokines, which could also play a role. In other models, TLR4 signaling has been shown to mediate cell migration through the action of growth factors and cytokines.

From a therapeutic perspective, the study's finding that exogenous HMGB1 treatment did not further promote OPC migration suggests that it may not be beneficial for WMS recovery, at least concerning the OPC migration step in this specific model. However, it's crucial to consider the administration site and timing of treatments, as these factors can significantly impact therapeutic outcomes.

This study indicates caution regarding consuming food supplements like licorice (containing glycyrrhizin) after a WMS injury. Glycyrrhizin's presence may interfere with endogenous HMGB1 levels and influence OPC migration. However, it's crucial to note that the study didn't specifically investigate glycyrrhizin's effects on OPC migration in vivo. Therefore, this cautionary message was not conveyed in my previous blog to readers or the public without further research to support its validity.

Overall, this study is intriguing as it challenges the conventional understanding of HMGB1's role in stroke and emphasizes the complexity of its actions. It urges caution when contemplating HMGB1-blocking therapies, such as glycyrrhizin, and further research is essential to fully grasp the implications for stroke treatments.

Thank you again for your insightful comments.-Hansen

The important thing is not to stop questioning." - Albert Einstein