Local immune cell contributions to fracture healing in aged individuals – A novel role for interleukin 22

Bucher, Christian H.; Berkmann, Julia C.; Burkhardt, Lisa-Marie; Paschke, Carolin; Schlundt, Claudia; Lang, Annemarie; Wolter, Angelique; Damerau, Alexandra; Geißler, Sven; Volk, Hans‐Dieter; Duda, Georg N.; Schmidt‐Bleek, Katharina

doi:10.1038/s12276-022-00834-9

Cited by 10 publications

(13 citation statements)

References 76 publications

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“…Flow analysis was run on a CytoFlex LX system (BeckmanCoulter, Brea, CA, USA) and population gating and tSNE analysis were performed with FlowJo (BD Biosciences, Franklin Lakes, NJ, USA). The gating strategy performed as previously published 91 . Outliers were identified with the ROUT method and excluded from the analysis.…”

Section: Methodsmentioning

confidence: 99%

Odd skipped-related 1 controls the pro-regenerative response of fibro-adipogenic progenitors

et al. 2023

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Skeletal muscle regeneration requires the coordinated interplay of diverse tissue-resident- and infiltrating cells. Fibro-adipogenic progenitors (FAPs) are an interstitial cell population that provides a beneficial microenvironment for muscle stem cells (MuSCs) during muscle regeneration. Here we show that the transcription factor Osr1 is essential for FAPs to communicate with MuSCs and infiltrating macrophages, thus coordinating muscle regeneration. Conditional inactivation of Osr1 impaired muscle regeneration with reduced myofiber growth and formation of excessive fibrotic tissue with reduced stiffness. Osr1-deficient FAPs acquired a fibrogenic identity with altered matrix secretion and cytokine expression resulting in impaired MuSC viability, expansion and differentiation. Immune cell profiling suggested a novel role for Osr1-FAPs in macrophage polarization. In vitro analysis suggested that increased TGFβ signaling and altered matrix deposition by Osr1-deficient FAPs actively suppressed regenerative myogenesis. In conclusion, we show that Osr1 is central to FAP function orchestrating key regenerative events such as inflammation, matrix secretion and myogenesis.

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Section: Methodsmentioning

confidence: 99%

Odd skipped-related 1 controls the pro-regenerative response of fibro-adipogenic progenitors

et al. 2023

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“…Interestingly, HIF1α+ cells reappeared 7 days after injury. In addition, the macrophage plasticity steering the healing process is significantly affected by the inflammation of the adaptive immune system, where classically activated M1 macrophages persist longer as the predominant phenotype in the early healing phase [ 11 ]. M1 macrophages secrete high amounts of VEGF, thus inducing the re-vascularization of the fracture gap; however, M2 macrophages stabilize the newly formed vessels by secreting growth factors like basic fibroblastic growth factor (bFGF) or platelet-derived growth factor-BB (PDGF-BB) [ 13 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

“…During this healing cascade, immune cells play a key role [ 9 , 10 , 11 ]. They are among the first cells infiltrating a fracture zone after injury [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Complex Spatio-Temporal Interplay of Distinct Immune and Bone Cell Subsets during Bone Fracture Healing

Schlundt,

Saß,

Bucher

et al. 2023

Cells

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Background: The healing of a bone injury is a highly complex process involving a multitude of different tissue and cell types, including immune cells, which play a major role in the initiation and progression of bone regeneration. Methods: We histologically analyzed the spatio-temporal occurrence of cells of the innate immune system (macrophages), the adaptive immune system (B and T lymphocytes), and bone cells (osteoblasts and osteoclasts) in the fracture area of a femoral osteotomy over the healing time. This study was performed in a bone osteotomy gap mouse model. We also investigated two key challenges of successful bone regeneration: hypoxia and revascularization. Results: Macrophages were present in and around the fracture gap throughout the entire healing period. The switch from initially pro-inflammatory M1 macrophages to the anti-inflammatory M2 phenotype coincided with the revascularization as well as the appearance of osteoblasts in the fracture area. This indicates that M2 macrophages are necessary for the restoration of vessels and that they also play an orchestrating role in osteoblastogenesis during bone healing. The presence of adaptive immune cells throughout the healing process emphasizes their essential role for regenerative processes that exceeds a mere pathogen defense. B and T cells co-localize consistently with bone cells throughout the healing process, consolidating their crucial role in guiding bone formation. These histological data provide, for the first time, comprehensive information about the complex interrelationships of the cellular network during the entire bone healing process in one standardized set up. With this, an overall picture of the spatio-temporal interplay of cellular key players in a bone healing scenario has been created. Conclusions: A spatio-temporal distribution of immune cells, bone cells, and factors driving bone healing at time points that are decisive for this process—especially during the initial steps of inflammation and revascularization, as well as the soft and hard callus phases—has been visualized. The results show that the bone healing cascade does not consist of five distinct, consecutive phases but is a rather complex interrelated and continuous process of events, especially at the onset of healing.

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“…Upon recruitment, systemically-derived monocytes differentiate into macrophages and dendritic cells. Dendritic cells are present during the early phases of fracture healing, and express inflammatory cytokines (IL-6, IL-12, TNF-a, IL-10) ( 20 – 24 ). Furthermore, CD8+ dendritic cells are known to stimulate CD8+ T cells ( 20 ).…”

Section: Hematoma Formation and Inflammatory Phasementioning

confidence: 99%

“…Dendritic cells are present during the early phases of fracture healing, and express inflammatory cytokines (IL-6, IL-12, TNF-a, IL-10) ( 20 – 24 ). Furthermore, CD8+ dendritic cells are known to stimulate CD8+ T cells ( 20 ). Early on, macrophages remove cellular debris and secrete inflammatory cytokines including IL-1, TNF-α, IL-6, chemokine (C-X-C motif) ligand (CXCL) 8, CXCL12, and MCP-1 ( 25 – 27 ).…”

Section: Hematoma Formation and Inflammatory Phasementioning

confidence: 99%

Temporal dynamics of immune-stromal cell interactions in fracture healing

Capobianco,

Hankenson,

Knights

2024

Front. Immunol.

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Bone fracture repair is a complex, multi-step process that involves communication between immune and stromal cells to coordinate the repair and regeneration of damaged tissue. In the US, 10% of all bone fractures do not heal properly without intervention, resulting in non-union. Complications from non-union fractures are physically and financially debilitating. We now appreciate the important role that immune cells play in tissue repair, and the necessity of the inflammatory response in initiating healing after skeletal trauma. The temporal dynamics of immune and stromal cell populations have been well characterized across the stages of fracture healing. Recent studies have begun to untangle the intricate mechanisms driving the immune response during normal or atypical, delayed healing. Various in vivo models of fracture healing, including genetic knockouts, as well as in vitro models of the fracture callus, have been implemented to enable experimental manipulation of the heterogeneous cellular environment. The goals of this review are to (1): summarize our current understanding of immune cell involvement in fracture healing (2); describe state-of-the art approaches to study inflammatory cells in fracture healing, including computational and in vitro models; and (3) identify gaps in our knowledge concerning immune-stromal crosstalk during bone healing.

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Local immune cell contributions to fracture healing in aged individuals – A novel role for interleukin 22

Cited by 10 publications

References 76 publications

Odd skipped-related 1 controls the pro-regenerative response of fibro-adipogenic progenitors

Odd skipped-related 1 controls the pro-regenerative response of fibro-adipogenic progenitors

Complex Spatio-Temporal Interplay of Distinct Immune and Bone Cell Subsets during Bone Fracture Healing

Temporal dynamics of immune-stromal cell interactions in fracture healing

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