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Differentiated fibrocytes assume a functional mesenchymal phenotype with regenerative potential.

ABSTRACT: Fibrocytes (FCs) are hematopoietic lineage cells that migrate to sites of injury, transition to a mesenchymal phenotype, and help to mediate wound repair. Despite their relevance to human fibrotic disorders, there are few data characterizing basic FC biology. Herein, using proteomic, bioenergetic, and bioengineering techniques, we conducted deep phenotypic characterization of differentiating and mature FCs. Differentiation was associated with metabolic reprogramming that favored oxidative phosphorylation. Mature FCs had distinct proteomes compared to classic mesenchymal cells, formed functional stromae that supported epithelial maturation during in vitro organotypic culture, and exhibited in vivo survival and self-tolerance as connective tissue isografts. In an in vitro scratch assay, FCs promoted fibroblast migration and wound closure by paracrine signaling via the chemokine CXCL8 (interleukin-8). These findings characterize important aspects of FC differentiation and show that, in addition to their role in wound healing, FCs hold potential as an easily isolated autologous cell source for regenerative medicine.

SUBMITTER: Ling C

PROVIDER: S-EPMC6506241 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Differentiated fibrocytes assume a functional mesenchymal phenotype with regenerative potential.

Ling Changying C Nishimoto Kohei K Rolfs Zach Z Smith Lloyd M LM Frey Brian L BL Welham Nathan V NV

Science advances 20190508 5

Fibrocytes (FCs) are hematopoietic lineage cells that migrate to sites of injury, transition to a mesenchymal phenotype, and help to mediate wound repair. Despite their relevance to human fibrotic disorders, there are few data characterizing basic FC biology. Herein, using proteomic, bioenergetic, and bioengineering techniques, we conducted deep phenotypic characterization of differentiating and mature FCs. Differentiation was associated with metabolic reprogramming that favored oxidative phosph ...[more]

PMID: 31086819

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Project description:BackgroundMesenchymal stem cells (MSCs) have shown promising results in stimulating cartilage repair and in the treatment of osteoarthritis (OA). However, the fate of the MSCs after intra-articular injection and their role in cartilage regeneration is not clear. To address these questions, this study investigated (1) homing of labeled human adipose tissue derived integrin α10β1-selected MSCs (integrin α10-MSCs) to a cartilage defect in a rabbit model and (2) the ability of the integrin α10-MSCs to differentiate to chondrocytes and to produce cartilage matrix molecules in vivo.DesignIntegrin α10-MSCs were labeled with superparamagnetic iron oxide nanoparticles (SPIONs) co-conjugated with Rhodamine B to allow visualization by both MRI and fluorescence microscopy. A cartilage defect was created in the articular cartilage of the intertrochlear groove of the femur of rabbits. Seven days post-surgery, labeled integrin α10-MSCs or vehicle were injected into the joint. Migration and distribution of the SPION-labeled integrin α10-MSCs was evaluated by high-field 9.4 T MRI up to 10 days after injection. Tissue sections from the repair tissue in the defects were examined by fluorescence microscopy.ResultsIn vitro characterization of the labeled integrin α10-MSCs demonstrated maintained viability, proliferation rate and trilineage differentiation capacity compared to unlabeled MSCs. In vivo MRI analysis detected the labeled integrin α10-MSCs in the cartilage defects at all time points from 12 h after injection until day 10 with a peak concentration between day 1 and 4 after injection. The labeled MSCs were also detected lining the synovial membrane at the early time points. Fluorescence analysis confirmed the presence of the labeled integrin α10-MSCs in all layers of the cartilage repair tissue and showed co-localization between the labeled cells and the specific cartilage molecules aggrecan and collagen type II indicating in vivo differentiation of the MSCs to chondrocyte-like cells. No adverse effects of the α10-MSC treatment were detected during the study period.ConclusionOur results demonstrated migration and homing of human integrin α10β1-selected MSCs to cartilage defects in the rabbit knee after intra-articular administration as well as chondrogenic differentiation of the MSCs in the regenerated cartilage tissue.

Project description:As tissue engineering and regenerative medicine have evolved recently, stem cell therapy has been investigated in the field of impaired wound healing. Several studies have reported that mesenchymal stem cells derived from various tissues including bone marrow and adipose tissue can exert the regenerative efficacy in the wound healing. Previously, we have demonstrated the isolation and characterization of tonsil-derived mesenchymal stem cells (TMSCs) with excellent proliferative property. In the present study, we aimed to evaluate the regenerative efficacy of TMSCs in the wound healing process. Two distinct cutaneous surgical defects were generated in the dorsum of mice. Each wound was treated with TMSCs or phosphate-buffered saline (PBS), respectively. After sacrifice, the skin and subcutaneous tissues around the surgical defect were harvested and assessed for inflammation, re-epithelialization, dermal regeneration, and granulation tissue formation. The administration of TMSCs into wound beds significantly promoted the repair of surgical defects in mice. Especially, TMSCs efficiently contributed to the attenuation of excessive inflammation in the surgical lesion, as well as the augmentation of epidermal and dermal regeneration. To elucidate the underlying mechanisms, TMSCs were analyzed for their potency in immunomodulatory ability on immune cells, stimulatory effect on the proliferation of keratinocytes, and fibroblasts, as well as the regulation of fibroblast differentiation. TMSCs inhibited the non-specific or T-cell-specific proliferation of peripheral blood mononuclear cells, as well as the M1 polarization of macrophage-like cells. Moreover, TMSCs augmented the proliferation of skin-constituting fibroblasts and keratinocytes while they suppressed the differentiation of fibroblasts into myofibroblasts. Taken together, our findings demonstrate the regenerative potential of TMSCs in wound healing process through the regulation on inflammation, proliferation, and remodeling of various skin cells, implying that TMSCs can be a promising alternative for wound repair.

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Differentiated fibrocytes assume a functional mesenchymal phenotype with regenerative potential.

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Differentiated fibrocytes assume a functional mesenchymal phenotype with regenerative potential.

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