CD8<sup>+</sup> T-cell plasticity regulates vascular regeneration in type-2 diabetes

Cai, Liang; Yang, Kevin Yi; Chan, Vicken W.; Li, Xisheng; Fung, Tiffany H.W.; Wu, Yaqing; Tian, Xiao Yu; Huang, Yü; Qin, Ling; Lau, James Y.; Lui, Kathy O.

doi:10.7150/thno.40663

Cited by 30 publications

(39 citation statements)

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“…The angiogenic and arteriogenic potency of monocytes is well described [17,18,20,21,54]. More recently several studies also indicate an angiogenic function of speci c limphocytes populations [25,[55][56][57][58].…”

Section: Discussionmentioning

confidence: 93%

The use of Peripheral Blood-Mononuclear Cells in Scleroderma patients: an observational preliminary study

Carella

Rossi

Ribuffo

et al. 2020

Preprint

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Background Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by vasculopathy and excessive production of collagen, which lead to skin and visceral fibrosis. The aim of our study is to assess the potential benefits of peripheral blood mononuclear cells (PB-MNCs) implants in the treatment of clinical manifestations such as mouth impairment, hand disability, digital ulcers and Raynaud’s phenomenon in Scleroderma patients. Methods From February 2016 to May 2019, 10 female patients were enrolled from the outpatient clinic of the Plastic Surgery Unit of Sapienza University of Rome. Parameters evaluated were: patients’ disability, using the Health Assessment Questionnaire (HAQ) disability index (DI) and the scleroderma HAQ (sHAQ); mouth opening capacity, by measuring the maximum interincisal distance and the mouth perimeter; hand mobility, assessed with clinical exam and the Hand Mobility in Scleroderma (HAMIS) scale; Raynaud’s phenomenon, evaluated through nailfold capillaroscopy; digital ulcers, examined through their features and incidence of appearance. SPSS software was used for a simple descriptive statistical analysis performed by the Student's paired t-test. P values less than 0.05 were considered statistically significant. Results The treatment showed a significant improvement of all the parameters evaluated at 1-year follow-up, it was well-tolerated by all the patients and the only complications noticed were small areas of ecchymosis. Conclusions Our results suggest that PB-MNCs injection could represent a treatment option to take into account for SSc patients. The procedure we used is easy and fast to perform, minimally invasive and not-operator dependent. We hope our observational and preliminary study could be considered as a starting point for further research studies.

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Section: Discussionmentioning

confidence: 93%

The use of Peripheral Blood-Mononuclear Cells in Scleroderma patients: an observational preliminary study

Carella

Rossi

Ribuffo

et al. 2020

Preprint

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“…In order to understand the heterogeneity of different T-cell subsets of the regenerating and non-regenerating hearts in response to myocardial injury, we performed droplet-based genome-wide single-cell transcriptomic profiling (scRNA-seq) as recently described by us 6 , 14 , 15 . At day 7 after injury, we purified CD45 + CD3 + T-cells from the hearts of ICR mice that underwent CI at P3 and P8 by flow cytometry; and captured the transcriptomic landscape of about ~1,123 and ~2,167 cells by scRNA-seq, respectively.…”

Section: Resultsmentioning

confidence: 99%

Specific ablation of CD4⁺ T-cells promotes heart regeneration in juvenile mice

Li¹,

Cai²,

Yang³

et al. 2020

Theranostics

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Unlike adult cardiomyocytes, neonatal cardiomyocytes can readily proliferate that contributes to a transient regenerative potential after myocardial injury in mice. We have recently reported that CD4 + regulatory T-cells promote this process; however, the role of other CD4 + T-cell subsets as well as CD8 + T-cells in postnatal heart regeneration has been less studied. Methods: by comparing the regenerating postnatal day (P) 3 and the non-regenerating P8 heart after injury, we revealed the heterogeneity of CD4 + and CD8 + T-cells in the myocardium through single cell analysis. We also specifically ablated CD4 + and CD8 + T-cells using the lytic anti-CD4 and -CD8 monoclonal antibodies, respectively, in juvenile mice at P8 after myocardial injury. Results : we observe significantly more CD4 + FOXP3 - conventional T-cells in the P8 heart when compared to that of the P3 heart within a week after injury. Surprisingly, such a difference is not seen in CD8 + T-cells that appear to have no function as their depletion does not reactivate heart regeneration. On the other hand, specific ablation of CD4 + T-cells contributes to mitigated cardiac fibrosis and increased cardiomyocyte proliferation after injury in juvenile mice. Single-cell transcriptomic profiling reveals a pro-fibrotic CD4 + T-cell subset in the P8 but not P3 heart. Moreover, there are likely more Th1 and Th17 cells in the P8 than P3 heart. We further demonstrate that cytokines of Th1 and Th17 cells can directly reduce the proliferation and increase the apoptosis of neonatal cardiomyocytes. Moreover, ablation of CD4 + T-cells can directly or indirectly facilitate the polarization of macrophages away from the pro-fibrotic M2-like signature in the juvenile heart. Nevertheless, ablation of CD4 + T-cells alone does not offer the same protection in the adult heart after myocardial infarction, suggesting a developmental change of immune cells including CD4 + T-cells in the regulation of age-related mammalian heart repair. Conclusions : our results demonstrate that ablation of CD4 + but not CD8 + T-cells promotes heart regeneration in juvenile mice; and CD4 + T-cells play a distinct role in the regulation of heart regeneration and repair during development.

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“…66 More recently, our group has also demonstrated the heterogeneity of CD8 + T cells in the skeletal muscles of healthy (Lepr db/+ ) and obesity-related diabetic (Lepr db/db ) mice after ischemic injury. 5 We showed by scRNA-Seq that there were 3 subsets of CD8 + T cells and trajectories inference by Monocle revealed 2 alternative fates of CD8 + T cells of healthy and diabetic mice in response to the ischemic injury: CD8 + T cells differentiated from an angiogenic, central memory precursor subset to a tissue-resident memory subset in healthy mice, whereas the angiogenic precursor subset is skewed to an effector and effector memory subset in diabetic mice. Although trajectory inferred from scRNA-Seq data could provide temporal information during many comprehensive immunologic processes, these transcriptomebased data should be validated by users to confirm expression at the protein level possibly with in vivo lineage tracing models to record their lineage commitment during immune cell development.…”

Section: Reconstructing the Temporal Dynamic Of Immune Cells In Tissumentioning

confidence: 89%

Single-cell transcriptomics uncover distinct innate and adaptive cell subsets during tissue homeostasis and regeneration

Yang

Lui

2020

Journal of Leukocyte Biology

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Recently, immune cell-mediated tissue repair and regeneration has been an emerging paradigm of regenerative medicine. Immune cells form an essential part of the wound as induction of inflammation is a necessary step to elicit tissue healing. Rapid progress in transcriptomic analyses by high-throughput next-generation sequencing has been developed to study gene regulatory network and establish molecular signatures of immune cells that could potentially predict their functional roles in tissue repair and regeneration. However, the identification of cellular heterogeneity especially on the rare cell subsets has been limited in transcriptomic analyses of bulk cell populations. Therefore, genome-wide, single-cell RNA sequencing (scRNA-Seq) has offered an unprecedented approach to unravel cellular diversity and to study novel immune cell populations involved in tissue repair and regeneration through unsupervised sampling of individual cells without the need to rely on prior knowledge about cell-specific markers. The analysis of gene expression patterns at a single-cell resolution also holds promises to uncover the mechanisms and therefore the development of therapeutic strategy promoting immunoregenerative medicine. In this review, we will discuss how scRNA-Seq facilitates the characterization of immune cells, including macrophages, innate lymphoid cells and T and B lymphocytes, discovery of immune cell heterogeneity, identification of novel subsets, and tracking of developmental trajectories of distinct immune cells during tissue homeostasis, repair, and regeneration.

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CD8⁺ T-cell plasticity regulates vascular regeneration in type-2 diabetes

Cited by 30 publications

References 0 publications

The use of Peripheral Blood-Mononuclear Cells in Scleroderma patients: an observational preliminary study

The use of Peripheral Blood-Mononuclear Cells in Scleroderma patients: an observational preliminary study

Specific ablation of CD4⁺ T-cells promotes heart regeneration in juvenile mice

Single-cell transcriptomics uncover distinct innate and adaptive cell subsets during tissue homeostasis and regeneration

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CD8+ T-cell plasticity regulates vascular regeneration in type-2 diabetes

Cited by 30 publications

References 0 publications

The use of Peripheral Blood-Mononuclear Cells in Scleroderma patients: an observational preliminary study

The use of Peripheral Blood-Mononuclear Cells in Scleroderma patients: an observational preliminary study

Specific ablation of CD4+ T-cells promotes heart regeneration in juvenile mice

Single-cell transcriptomics uncover distinct innate and adaptive cell subsets during tissue homeostasis and regeneration

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CD8⁺ T-cell plasticity regulates vascular regeneration in type-2 diabetes

Specific ablation of CD4⁺ T-cells promotes heart regeneration in juvenile mice