Schwann cells contribute to keloid formation

et al. 2022

Preprint

Self Cite

Recently, a specific Schwann cell type with pro-fibrotic and tissue regenerative properties has been identified that contributes to keloid formation. In the present study, we have re-analysed published single cell RNA sequencing (scRNAseq) studies of keloids, healthy skin and normal scars to reliably determine the specific gene expression profile of the keloid-specific Schwann cell type in more detail. We were able to confirm the presence of the repair-like, pro-fibrotic Schwann cell type in the datasets of all three studies and identified a specific gene set for these Schwann cells. In contrast to keloids, in normal scars the number of Schwann cells was neither increased nor was their gene expression profile distinctly different from Schwann cells of normal skin. In addition, our bioinformatics analysis provided evidence for a role of transcription factors of the kruppel-like factor family and members of the immediate early response genes, in the de-differentiation process of keloidal Schwann cells. Together, our analysis strengthens the role of the pro-fibrotic Schwann cell type in the formation of keloids. Knowledge on the exact gene expression profile of these Schwann cells will facilitate their identification in other organs and diseases.

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The transcriptional profile of keloidal Schwann cells

Direder

Wielscher

et al. 2022

Preprint

Self Cite

“…Moreover, numerous studies support that the highly adaptive cellular state of SCs plays a role in pathological conditions such as neuropathies and tumor development (Azam & Pecot, 2016; Bunimovich, Keskinov, Shurin, & Shurin, 2017; Direder et al, 2021; Weiss et al, 2021). We have recently shown that tumor-associated SCs in neuroblastic tumors adopt a similar phenotype as upon nerve injury and exert anti-proliferative and pro-differentiating effects through the release of until then unknown neurotrophins, such as EGFL8 (Ambros et al, 1996; Crawford et al, 2001; Direder et al, 2021). As knowledge on the involvement of SCs during regeneration and pathologies is continuously expanding, their immunomodulatory potential gains increasing interest (Armati, Pollard, & Gatenby, 1990; Hörste, Hu, Hartung, Lehmann, & Kieseier, 2008; Zhang et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…In this dedicated repair cell state, SCs re-enter the cell cycle and execute specialized functions to coordinate the multi-step process of nerve regeneration, such as the recruitment of immune cells, the breakdown of myelin debris, remodeling of the extracellular matrix, and the expression of neurotrophic and neuritogenic factors for axon survival, regrowth, and guidance (Gomez-Sanchez et al, 2015; Jang et al, 2016; Jessen & Mirsky, 2016; Nocera & Jacob, 2020; Tofaris, Patterson, Jessen, & Mirsky, 2002; Weiss et al, 2016). Moreover, numerous studies support that the highly adaptive cellular state of SCs plays a role in pathological conditions such as neuropathies and tumor development (Azam & Pecot, 2016; Bunimovich, Keskinov, Shurin, & Shurin, 2017; Direder et al, 2021; Weiss et al, 2021). We have recently shown that tumor-associated SCs in neuroblastic tumors adopt a similar phenotype as upon nerve injury and exert anti-proliferative and pro-differentiating effects through the release of until then unknown neurotrophins, such as EGFL8 (Ambros et al, 1996; Crawford et al, 2001; Direder et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Human repair-related Schwann cells adopt functions of antigen-presenting cells in vitro

Berner

Sorger

et al. 2022

Preprint

Self Cite

The plastic potential of Schwann cells (SCs) is increasingly recognized to play a role after nerve injury and in diseases of the peripheral nervous system. In addition, reports on the interaction between SCs and immune cells indicate their involvement in inflammatory processes. However, data about the immunocompetence of human SCs are primarily derived from neuropathies and it is currently unknown whether SCs directly regulate an adaptive immune response after nerve injury. Here, we performed a comprehensive analysis of the immunomodulatory capacities of human repair-related SCs (hrSCs), which recapitulate SC response to nerve injury in vitro. We used our previously established protocol for the culture of primary hrSCs from human peripheral nerves and analyzed the transcriptome, secretome, and cell surface proteins for signatures and markers relevant in innate and adaptive immunity, performed phagocytosis assays, and monitored T-cell subset activation in co-cultures with autologous human T-cells. Our findings show that hrSCs are highly phagocytic, which is in line with high MHCII expression. In addition, hrSCs express co-regulatory molecules, such as CD40, CD80, B7H3, CD58, CD86, HVEM, release a plethora of chemoattractants, matrix remodelling proteins and pro- as well as anti-inflammatory cytokines, and upregulate the T-cell inhibiting PD-L1 molecule upon pro-inflammatory stimulation with IFNgamma;. Furthermore, hrSC contact reduced the number and activation status of allogenic CD4+ and CD8+ T-cells. This study demonstrates that hrSCs possess features and functions typical for professional antigen presenting cells in vitro, and suggest a new role of these cells as negative regulators of T-cell immunity during nerve regeneration.

Human repair‐related Schwann cells adopt functions of antigen‐presenting cells in vitro

Berner

Sorger

et al. 2022

Glia

Self Cite

The plastic potential of Schwann cells (SCs) is increasingly recognized to play a role after nerve injury and in diseases of the peripheral nervous system. Reports on the interaction between immune cells and SCs indicate their involvement in inflammatory processes. However, the immunocompetence of human SCs has been primarily deduced from neuropathies, but whether after nerve injury SCs directly regulate an adaptive immune response is unknown. Here, we performed comprehensive analysis of immunomodulatory capacities of human repair‐related SCs (hrSCs), which recapitulate SC response to nerve injury in vitro. We used our well‐established culture model of primary hrSCs from human peripheral nerves and analyzed the transcriptome, secretome, and cell surface proteins for pathways and markers relevant in innate and adaptive immunity, performed phagocytosis assays, and monitored T‐cell subset activation in allogeneic co‐cultures. Our findings show that hrSCs are phagocytic, which is in line with high MHCII expression. Furthermore, hrSCs express co‐regulatory proteins, such as CD40, CD80, B7H3, CD58, CD86, and HVEM, release a plethora of chemoattractants, matrix remodeling proteins and pro‐ as well as anti‐inflammatory cytokines, and upregulate the T‐cell inhibiting PD‐L1 molecule upon pro‐inflammatory stimulation with IFNγ. In contrast to monocytes, hrSC alone are not sufficient to trigger allogenic CD4+ and CD8+ T‐cells, but limit number and activation status of exogenously activated T‐cells. This study demonstrates that hrSCs possess features and functions typical for professional antigen‐presenting cells in vitro, and suggest a new role of these cells as negative regulators of T‐cell immunity during nerve regeneration.