Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript addresses an interesting and potentially important topic, particularly because the interaction between glial development, metabolism, white matter injury and myelination is highly relevant to neonatal brain vulnerability. The attempt to integrate cellular biology, metabolism, neuroimaging and omics has its potential. However, in its current form, I would recommend major revision because of the following:

There is a statement: "In neonates, astrocytes develop between 26th–27th weeks of gestation". Later, the manuscript itself cites literature describing astrocytogenesis substantially earlier in development and discusses astrocytes at approximately 20 weeks' gestation. This creates a conceptual inconsistency. I suggest reframing the developmental question to which cellular and metabolic mechanisms support oligodendrocyte maturation before astrocytes acquire their mature functional phenotype.

The authors repeatedly use terms such as "myelin loss", "demyelination", "myelination failure", "delayed myelination", and "impaired myelination" in a developing brain context. My opinion is that these concepts are not interchangeable.

The section on oligodendrocyte immunology is disproportionately long to its relevance to the review. The space given to MHC expression, antigen presentation and inflammatory cytokines produced by oligodendrocytes in the manuscript interrupts the metabolic narrative. I suggest reducing this subsection.

The imaging section is too detailed relative to the purpose of the review. If the authors decide to keep this section in its full length, I recommend redesigning it with some other answers, like what are the limitations of imaging, whether it has been validated against histopathology or molecular measures or whether it can distinguish maturation from injury.

The authors should ensure that every major biological assertion in the Figure 1 is supported by the manuscript or references. I would recommend simplifying the figure.

Ranvier nodes are not cells, yet they are presented under "Cell name" in Table 1.

When you performed literature search in PubMed/MEDLINE, Embase and CINAHL, please specify if there were language restrictions, approximate date of the final search for example.

Language and grammar require extensive editing.

I recommend avoiding subjective language with phrases such as: "most promising approach"; "brilliantly synthetized"; etc.

You should define every abbreviation consistently.

The reference list should be checked for completeness and bibliographic accuracy.

Comments for author File: Comments.pdf

Comments on the Quality of English Language

There are numerous grammatical and stylistic errors throughout the manuscript. Examples include Glia cells, olig2 directs astrocytes, preterm newbron, asyncronised, oncomes, Periferic Nervous System, etc.

Author Response

We sincerely thank the Editor and the Reviewers for their careful evaluation of our manuscript and for their constructive comments. We have revised the manuscript accordingly. In particular, we have clarified the developmental framing of astrocyte–oligodendrocyte interactions, strengthened the distinction between evidence derived from the developing human brain and evidence from experimental or adult populations, clarified the terminology related to myelination, expanded the methodological description of the narrative search, critically reframed the imaging and radiomics sections, and explicitly identified the Crossword and Foil Effects as hypothesis-generating conceptual frameworks. The manuscript has also undergone language and reference consistency revision.

Comment 1. The timing of astrocyte development appears inconsistent with the central research question. The question should be reframed toward the mechanisms supporting oligodendrocyte maturation before astrocytes acquire their mature functional phenotype.

Response: We thank the Reviewer for this important observation. We agree that the original formulation could be interpreted as implying the absence of astrocytes rather than the progressive acquisition of mature astrocytic functions. We therefore reformulated the research question as: “Who supports oligodendrocyte maturation and white-matter metabolism before mature astrocytic functions are fully established?” This formulation more accurately reflects the developmental problem addressed by the review. 

We further strengthened the developmental discussion by distinguishing astrocyte development from mature astrocytic functionality and by discussing oligodendrocyte precursor vulnerability and maturation in the very preterm developmental period. 

Comment 2. The terms “myelin loss”, “demyelination”, “myelination failure”, and “delayed/impaired myelination” should not be used interchangeably.

Response: We thank the Reviewer for this important clarification. We carefully reviewed the terminology throughout the manuscript to avoid presenting demyelination, myelin loss, myelination failure, and delayed or impaired myelination as interchangeable biological phenomena. Where these terms are retained, they reflect the specific process or outcome described in the cited study rather than being used as synonyms.

To make this principle explicit, we added the following statement to the Search Strategy/Terminology section: “Throughout this review, demyelination, myelin loss, delayed or impaired myelination, and myelination failure are used according to the specific biological process or outcome described in the cited studies and should not be interpreted as interchangeable terms, particularly in the developing brain.” 

Comment 3. The discussion of the immunological role of oligodendrocytes is disproportionately long.

Response: We agree and have condensed this discussion to maintain focus on the central astrocyte–oligodendrocyte axis. The revised text now briefly acknowledges the potential contribution of oligodendrocytes to local immune regulation while linking this aspect specifically to the inflammatory and haemodynamic environment in which oligodendrocyte maturation and myelination occur in the developing brain. 

Comment 4. The imaging/radiomics discussion is overly detailed and should more critically address limitations, validation, and the ability of imaging to distinguish maturation from injury.

Response: We thank the Reviewer and agree that the role of neuroimaging required clearer critical framing. We have revised this section to state explicitly that neuroimaging cannot directly resolve astrocyte–oligodendrocyte coupling in vivo. Instead, imaging provides complementary information concerning structural and maturational consequences in developing white matter. We now distinguish the information provided by QSM, SyMRI, cranial ultrasound, PET, and MRI-based myelin imaging and emphasize their modality-specific validation constraints. 

Radiomics has likewise been reframed as providing indirect imaging biomarkers rather than direct measures of astrocytic or oligodendroglial biology.

Comment 5. Major biological assertions in Figure 1 should be supported and the figure simplified where necessary.

Response: We thank the Reviewer. Figure 1 and its legend have been revised to clarify its intended function. The Crossword Effect is now explicitly presented as a hypothesis-generating conceptual framework integrating developmental, metabolic, cellular, imaging, and molecular dimensions discussed in the review, rather than as an experimentally validated mechanistic or causal model. 

Comment 6. Nodes of Ranvier are not cells.

Response: We agree and thank the Reviewer for identifying this error. Nodes of Ranvier have been removed from the table of cell types.

Comment 7. Please specify language restrictions and the approximate final search date.

Response: We have added both details. The revised Search Strategy states that articles were considered from inception to 10 September 2026 and that no language restriction was applied. 

Comment 8. The manuscript requires extensive English-language and grammatical editing.

Response: We thank the Reviewer. The manuscript has undergone extensive language editing to improve grammar, syntax, terminology, and readability while preserving the scientific meaning of the cited evidence.

Comment 9. Avoid subjective expressions such as “the most promising approach” and “brilliantly synthetized”.

Response: We agree. Subjective wording has been removed and replaced with neutral scientific language. The Introduction now describes the systems-biology approach and the neuro-glia-vascular framework without evaluative wording. 

Comment 10. Define abbreviations consistently.

Response: We thank the Reviewer. Abbreviations have been reviewed for consistency throughout the revised manuscript and are defined in context where appropriate.

Comment 11. References should be checked for completeness and accuracy.

Response: We agree. The reference list and corresponding in-text citations have been reviewed for consistency and bibliographic accuracy. Particularly, Bonato et al. has not yet any DOI as it is about to be published on Frontiers in Endocrinology.

Reviewer 2 Report

Comments and Suggestions for Authors

This is an interesting and clinically relevant topic, focusing on the evolving astrocyte–oligodendrocyte relationship and its role in white-matter vulnerability in preterm infants. The review brings together cellular, metabolic, imaging, and omics perspectives. However, a few issues need to be addressed before the manuscript can be considered for publication.

Major comments

1. Methodology needs more detail. The authors mention searching PubMed/Embase/CINAHL and using the SANRA framework, but do not provide the search dates, full search strings, eligibility criteria, or information on how many studies were identified and included. Even for a narrative review, providing these details would improve transparency.
2. The central question gets somewhat lost. The review opens by asking who supports oligodendrocyte maturation before astrocytes are fully mature, but subsequently covers imaging, radiomics, hyperbilirubinemia, and dysglycemia without consistently linking these topics back to the central question. A clearer connection between each section and the main research question would strengthen the review.
3. Evidence from different sources is blended together. Human, animal, and cell-culture findings are often presented side by side without a clear distinction. Please specify the experimental context of the evidence and avoid presenting findings from different models as directly equivalent.
4. The "Crossword Effect" and "Foil Effect" need clearer framing. These concepts are central to Figures 1 and 2, but it is not always clear which elements represent established biological mechanisms and which represent the authors' own conceptual interpretation. Please clarify their added value in relation to existing models and make the figure legends reflect this distinction more clearly.
5. Some claims appear stronger than the evidence supports. Several statements imply causal relationships between metabolic disturbances, glial dysfunction, impaired myelination, and neurodevelopmental outcomes, although some of the cited evidence is observational or associative. Please moderate the wording where appropriate and distinguish established mechanisms from proposed or hypothesis-generating mechanisms.
6. Imaging biomarkers are treated somewhat uniformly. MRI, QSM, ultrasound, SyMRI, PET, and radiomics provide different types of biological information and should not be considered interchangeable proxies for myelin. A more critical comparison of what each technique can and cannot reveal about myelination and glial biology would strengthen this section.
7. The rationale for including radiomics/ML studies needs to be clearer. These studies are described in considerable detail, including AUC values and classifiers, but their direct connection to the central astrocyte–oligodendrocyte question is not always apparent. Please clarify why these studies are relevant to the review and emphasize that radiomic features are indirect imaging biomarkers rather than direct measures of glial biology.
8. Table 1 needs revision. Nodes of Ranvier are not a cell type but specialized axonal domains, so their inclusion in a table of "key cells in myelination" should be reconsidered. In addition, the rationale for including Schwann cells should be clarified given that the review primarily focuses on the developing CNS, or the table should be reframed accordingly.

Minor comments

• The manuscript would benefit from professional English editing. There are several grammatical, subject–verb agreement, spelling, and word-choice issues (e.g., "glia cells," "strives," and "oncomes").
• Section titles such as "Sugar Babies" and "The Outsiders" are catchy but somewhat informal for a scientific review. More descriptive titles would improve readability.
• Some paragraphs cover several distinct concepts at once and would benefit from clearer organization and, where appropriate, subdivision.
• Please carefully check the reference list for completeness and consistency; for example, reference 72 appears incomplete.
• The conclusion would benefit from a clearer distinction between findings that are well supported by the literature and the authors' own conceptual interpretation.

Overall, the topic is relevant and the manuscript brings together a broad range of literature. Addressing the points above would improve the clarity, methodological transparency, and scientific rigor of the review.

 

Comments for author File: Comments.pdf

Author Response

eviewer 2

Major Comment 1. The methodology requires greater detail regarding search dates, search strategy, eligibility criteria, and study identification/inclusion.

Response: We thank the Reviewer for highlighting the importance of methodological transparency. We expanded the Search Strategy section to report the databases, search period, principal search concepts, language restrictions, and eligibility criteria. Eligibility was defined according to the population, biological exposure, and outcomes relevant to the review question: preterm and ill term neonates; glial processes potentially related to glial uncoupling, with particular attention to astrocyte–oligodendrocyte interactions; healthy term newborns as comparators when applicable; and neonatal brain injury and alterations of developmental myelination as outcomes of interest.

As this is a concept-driven narrative review rather than a systematic review, the literature search was iterative and based on combinations of relevant keywords rather than on a single prespecified systematic-review search string. A formal record of the total number of retrieved and screened records was therefore not maintained, and we chose not to retrospectively reconstruct study-flow counts that would not accurately represent the search process performed.

Major Comment 2. The central question becomes lost in sections dealing with imaging, radiomics, hyperbilirubinemia, and dysglycemia. These topics should be explicitly connected to the astrocyte–oligodendrocyte axis.

Response: We agree and have strengthened these conceptual links throughout the manuscript. Neuroimaging is now explicitly framed as providing information on structural and maturational consequences in developing white matter rather than direct measurements of astrocyte–oligodendrocyte coupling. Omics approaches are presented as complementary means of interrogating the molecular environment in which astrocyte–oligodendrocyte maturation occurs. 

Similarly, the radiomics section now states explicitly that these features are indirect imaging biomarkers and should not be interpreted as direct measures of astrocytic or oligodendroglial biology. The dysglycemia section has also been linked directly to the dependence of developing white matter on coordinated cellular energy handling and to the potential vulnerability of immature astrocyte–oligodendrocyte interactions during metabolic instability.

Major Comment 3. Evidence from humans, animal models, and cell cultures is blended together. These levels of evidence should be clearly distinguished and should not be treated as equivalent.

Response: We fully agree. We added an explicit methodological statement that evidence derived from experimental models and adult or elderly populations is used exclusively for secondary mechanistic comparison and is neither considered equivalent to nor directly generalizable to evidence from the developing human brain. 

We have also clarified the experimental origin of specific evidence where necessary. For example, the sacsin discussion now explicitly identifies the evidence as deriving from primary astrocyte-enriched cultures from the cerebral cortex of neonatal rats. Likewise, the section concerning very early development explicitly distinguishes premature mouse evidence, adult mouse evidence, and human neonatal autopsy findings. 

Major Comment 4. The Crossword and Foil Effects should be clearly distinguished from established biological mechanisms and identified as the authors’ conceptual interpretation.

Response: We thank the Reviewer and agree. Both concepts have now been explicitly described as hypothesis-generating frameworks intended to organize evidence rather than replace established biological knowledge. The main text states that the Crossword and Foil Effects are used to organize observations across different biological scales. 

The figure legends have also been revised accordingly. The Crossword Effect is explicitly described as not representing an experimentally validated mechanistic or causal model, while the Foil Effect is identified as the authors’ conceptual interpretation and not as an experimentally validated causal sequence. 

Major Comment 5. Causal claims should be moderated when the underlying evidence is observational or associative.

Response: We agree. We reviewed the relevant passages and moderated the interpretative framing where appropriate. In particular, the conceptual frameworks are now explicitly presented as hypothesis-generating rather than causal, and the conclusions use cautious language to distinguish interpretation from established evidence. The revised conclusion states that oligodendrocyte maturation “appears to emerge” within a developmentally changing division of labour and that perinatal injury “may disrupt” this organization. 

Major Comment 6. Imaging modalities are not interchangeable. The manuscript should critically compare what MRI, QSM, ultrasound, SyMRI, PET, and radiomics can and cannot reveal about myelination and glial biology.

Response: We agree and have substantially revised this section. We now explicitly state that these approaches should be considered complementary rather than interchangeable. The revised manuscript distinguishes QSM as primarily reflecting magnetic susceptibility sources, including iron-related changes; SyMRI as deriving quantitative tissue properties potentially related to maturation; cranial ultrasound as providing bedside structural and maturational information without directly quantifying myelin; and PET/MRI-based myelin imaging as interrogating distinct molecular or tissue properties subject to modality-specific validation constraints. 

Major Comment 7. The rationale for the radiomics/machine-learning section should be clearer and excessive classifier/AUC detail reduced.

Response: We thank the Reviewer. We revised this section to emphasize the biological rationale rather than classifier performance. Radiomics is now introduced as an extension of conventional imaging that extracts quantitative features potentially reflecting tissue heterogeneity. Importantly, the manuscript explicitly states that such features remain indirect biomarkers and cannot be interpreted as direct measures of astrocytic or oligodendroglial biology. The relevance of radiomics to the central review question is therefore framed in terms of tissue phenotype associated with altered white-matter development. 

Major Comment 8. Table 1 incorrectly includes the node of Ranvier as a cell, and the rationale for including Schwann cells in a CNS-focused review should be clarified or the table reframed.

Response: We agree. The node of Ranvier has been removed because it is an anatomical specialization rather than a cell. To maintain the table’s focus on the central nervous system and on the scope of the present review, Schwann cells have also been removed from the revised table.

Minor Comments. English language, informal section titles, paragraph organization, references, and distinction between supported findings and interpretation in the Conclusion should be revised.

Response: We thank the Reviewer. The manuscript has undergone language and organizational revision, and section headings have been reformulated in a more formal scientific style. References and abbreviations have been reviewed for consistency. Finally, the Conclusion has been rewritten to distinguish the interpretation emerging from the reviewed evidence from established findings and to provide a direct answer to the central research question.

Reviewer 3 Report

Comments and Suggestions for Authors

Thank you for the opportunity to review this manuscript. I found this review very interesting, particularly its integrated perspective on astrocyte–oligodendrocyte interactions during brain development.

A few minor points may further improve the manuscript:

1. The statements that astrocytes develop at approximately 26–27 weeks and that they are “not yet formed” before this period should be clarified. It may be more accurate to distinguish astrocyte presence from astrocytic maturation and acquisition of mature functions.
2. Although the inclusion of neurons, microglia, vascular components, and other cells is appropriate, the astrocyte–oligodendrocyte interaction should remain the central organizing axis throughout the review.
3. Please distinguish more clearly between evidence derived from the developing human brain, experimental developmental models, and adult neurological diseases, particularly when discussing proposed mechanisms.
4. The terminology regarding impaired/delayed myelination versus demyelination should be standardized, as these processes are biologically distinct in the developing preterm brain.
5. Some sections on radiomics, dysglycemia, and omics could be slightly condensed and more explicitly linked to astrocyte–oligodendrocyte coupling and myelination. The proposed “Crossword” and “Foil” effects should also be clearly identified as hypothesis-generating frameworks.
6. Table 1 should be revised, as the node of Ranvier is not a cell.
7. Careful English-language editing is recommended to improve grammar, terminology, and readability throughout the manuscript.

Author Response

Comment 1. Clarify the discussion around 26–27 weeks and the statement that astrocytes are “not yet formed”; distinguish cellular presence from functional maturation.

Response: We thank the Reviewer for this important distinction. We revised the manuscript to avoid equating cellular presence with mature astrocytic functionality. The research question now explicitly refers to the period “before mature astrocytic functions are fully established”, rather than implying that astrocytes are absent. Testo incollato The developmental section now discusses prenatal astrocytogenesis and subsequent maturation while separately addressing oligodendrocyte precursor vulnerability before 27 weeks of gestation. Testo incollato

Comment 2. The astrocyte–oligodendrocyte axis should remain central throughout the review.

Response: We agree. We strengthened the astrocyte–oligodendrocyte axis throughout the revised manuscript, including the developmental/metabolic section, the discussion of white-matter injury, the interpretation of imaging and omics findings, and the dysglycemia section. The revised manuscript now consistently frames these additional domains according to their relevance to astrocyte–oligodendrocyte maturation and developing white matter. Testo incollato

Comment 3. Clearly distinguish evidence from the developing human brain, experimental developmental models, and adult neurological disease.

Response: We agree and have made this distinction explicit. The Search Strategy now states that experimental and adult/elderly evidence is used only for secondary mechanistic comparison and is not considered equivalent to or directly generalizable to evidence from the developing human brain. Testo incollato

The developmental section also explicitly identifies evidence according to its biological context, including premature mouse brain, adult mouse studies, and human neonatal autopsy samples. Testo incollato

Comment 4. Standardize the distinction between impaired/delayed myelination and demyelination.

Response: We agree. Rather than treating these terms as synonyms, we retained the terminology corresponding to the biological process described in each cited source and added an explicit statement clarifying that demyelination, myelin loss, delayed or impaired myelination, and myelination failure should not be interpreted as interchangeable terms, particularly in the developing brain. Testo incollato

Comment 5. The radiomics, dysglycemia, and omics sections should be more explicitly linked to the central question, and the Crossword/Foil Effects should be identified as hypothesis-generating.

Response: We thank the Reviewer. These sections have been revised to make their relationship with the central astrocyte–oligodendrocyte question explicit. Omics is presented as a complementary approach to interrogating the molecular environment in which astrocyte–oligodendrocyte maturation occurs, while radiomics is explicitly described as providing indirect tissue-level biomarkers rather than cell-specific readouts. Testo incollato Dysglycemia is linked to coordinated cellular energy handling in developing white matter and to the vulnerability of immature astrocyte–oligodendrocyte interactions. Testo incollato

The Crossword and Foil Effects are now explicitly defined as hypothesis-generating frameworks used to organize evidence across biological scales. Testo incollato

Comment 6. The node of Ranvier is not a cell.

Response: We agree and have removed the node of Ranvier from the table.

Comment 7. The English language requires revision.

Response: We thank the Reviewer. The manuscript has undergone extensive English-language editing to improve grammar, syntax, clarity, and consistency while preserving the scientific content and source-specific terminology.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The revised manuscript has addressed several of the substantive conceptual problems from the previous version: the abstract is considerably more focused, the role of multiple cellular compartments is better acknowledged, and the discussion of pre-oligodendrocyte maturation arrest is much more appropriate for developmental white-matter injury.

Comments on the Quality of English Language

There are numerous grammatical and stylistic errors throughout the manuscript. Examples include Glia cells, olig2 directs astrocytes, preterm newbron, asyncronised, oncomes, Periferic Nervous System, etc.

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for addressing my comments and for the substantial revisions made to the manuscript. The revised version has adequately addressed the major methodological and conceptual concerns raised in the previous review. I have no further major comments and support publication of the manuscript.