Fibroblast heterogeneity: more than skin deep

Sorrell, J. Michael; Caplan, Arnold I.

doi:10.1242/jcs.01005

Cited by 443 publications

(395 citation statements)

References 127 publications

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“…The onychodermis is a specialized, CD10-positive/CD34-negative dermal tissue, underlying the keratinized plate of the nail, that is thought to play an important role in adhesion and production of hard keratins (36,37). We hypothesize that Lgr5-expressing cells within the onychodermis in the proximal nail fold and distal groove, are specialized dermal fibroblasts, which are a heterogeneous population of cells involved in the production of connective tissue/ extracellular matrix, as well as the facilitation of cellular communication and integrity between the dermis and epidermis (38). Dermal fibroblast properties and function can vary with their embryonic source and/or anatomical location.…”

Section: Discussionmentioning

confidence: 99%

Lgr6 marks nail stem cells and is required for digit tip regeneration

Lehoczky

Tabin

2015

Proc. Natl. Acad. Sci. U.S.A.

109

128

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The tips of the digits of some mammals, including human infants and mice, are capable of complete regeneration after injury. This process is reliant on the presence of the overlaying nail organ and is mediated by a proliferative blastema. Epithelial Wnt/β-catenin signaling has been shown to be necessary for mouse digit tip regeneration. Here, we report on Lgr5 and Lgr6 (leucine-rich repeat-containing G protein-coupled receptor 5 and 6), two important agonists of the Wnt pathway that are known to be markers of several epithelial stem cell populations. We find that Lgr5 is expressed in a dermal population of cells adjacent to the specialized epithelia surrounding the keratinized nail plate. Moreover, Lgr5-expressing cells contribute to this dermis, but not the blastema, during digit tip regeneration. In contrast, we find that Lgr6 is expressed within cells of the nail matrix portion of the nail epithelium, as well as in a subset of cells in the bone and eccrine sweat glands. Genetic lineage analysis reveals that Lgr6-expressing cells give rise to the nail during homeostatic growth, demonstrating that Lgr6 is a marker of nail stem cells. Moreover, Lgr6-expressing cells contribute to the blastema, suggesting a potential direct role for Lgr6-expressing cells during digit tip regeneration. This role is confirmed by analysis of Lgr6-deficient mice, which have both a nail and bone regeneration defect.

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Section: Discussionmentioning

confidence: 99%

Lgr6 marks nail stem cells and is required for digit tip regeneration

Lehoczky

Tabin

2015

Proc. Natl. Acad. Sci. U.S.A.

109

128

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“…Human skin connective tissue consists primarily of blood vessels, fibroblasts, and extracellular matrix (Sorrell & Caplan, 2004). To mimic this primary human dermal connective tissue structure, human dermal microvascular endothelial cells (HMEC-1) were co-cultured with primary human adult dermal fibroblasts (NHDF) in our 3D culture system, which contains collagen types I and III (Junqueira, Montes, Martins, & Joazeiro, 1983).…”

Section: Development Of Microvessels In a 3d Tissue Culture System Thmentioning

confidence: 99%

Origin of periendothelial cells in microvessels derived from human microvascular endothelial cells

Njauw

Zheng

et al. 2008

The International Journal of Biochemistry & Cell Biology

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In microvessels, periendothelial cells expressing alpha smooth muscle actin (αSMA) interact with the endothelial cells and are essential for vessel maturation and stabilization. In adult tissues, the cellular origin of the periendothelial cells is still not clear, in particular in humans. To determine the origin of human periendothelial cells, we used a recently-developed 3D co-culture system that mimics human skin connective tissue. This system is composed of normal human dermal fibroblasts (NHDF), human dermal microvascular endothelial cells (HMEC-1), and a collagen matrix. In this system, "microvessels" composed of an endothelial lumen with associated with periendothelial cells develop. Using this co-culture system, we (i) labelled fibroblasts with the vital dye CFDA-SE, cultured them with unlabeled endothelial cells, and observed that only endothelium-associated CFDA-SE-labelled cells express αSMA; (ii) infected endothelial cells with a retrovirus stably expressing eGFP, cultured them with unlabeled fibroblasts, and observed that cells expressing αSMA did not co-express eGFP, but were associated with the eGFP-expressing endothelial cells of the microvessels. Together, these results indicate that periendothelial cells arise by differentiation from fibroblasts and that they require interaction with endothelial cells to do so.

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“…20,21 Considering their location within the dermis, fibroblasts are divided into papillary (superficial dermis) and reticular (deep dermis), exhibiting different characteristics in terms of cell morphology, production of ECM and growth factors, among others. 22,23 Although no specific markers distinguish both types of fibroblasts, differences in gene expression patterns exist, with reticular fibroblasts exhibiting an increased expression of genes involved in cell motility and contraction, including calponin-1 and transglutaminase-2 (TG2), whereas papillary fibroblasts characteristically express genes involved in the immune response, such as netrin-1 and podoplanin (PDPN). 23 Regarding vascularization, papillary fibroblasts seem to support the formation of highly branched tubular structures in vitro, while reticular fibroblasts do not.…”

mentioning

confidence: 99%

Fibroblast-Endothelial Partners for Vascularization Strategies in Tissue Engineering

Costa‐Almeida

Gómez-Lázaro

Ramalho

et al. 2015

Tissue Engineering Part A

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Cell-based approaches have emerged as a promising therapy to achieve successful vascularization in tissue engineering. Since fibroblasts activation and migration is required for physiological events relying on angiogenesis, we hypothesize herein that different fibroblasts exhibit distinct capacity to promote capillary-like structures assembly, by mature and progenitor endothelial cells (ECs). Outgrowth endothelial cells (OECs) were isolated from human umbilical cord blood samples and characterized by immunofluorescence and imaging flow cytometry for endothelial markers. Coculture systems were established using either human umbilical vein ECs (HUVECs) or OECs with fibroblasts, being evaluated at 7, 14, and 21 days of culture. Two types of human dermal fibroblasts (HDF) were used, namely neonatal human foreskin fibroblasts-1 (HFF-1) and juvenile HDF. OECs expressed EC markers and formed capillary-like structures. HFF-1 exhibited higher expression of transglutaminase-2, while HDF exhibited a higher expression of a-smooth muscle actin (a-SMA) and podoplanin, which were not observed for HFF-1. Formation of capillary-like structures was only observed in cocultures with HDF and not with HFF-1. No significant differences were found between HDF and OECs or HUVECs cocultures. These findings suggest that HDF is a preferential cell source for promoting vascularization, either using mature or progenitor ECs, probably due to their higher expression of a-SMA and podoplanin, and increased synthesis of extracellular matrix. This work opens new research possibilities regarding the use of specific fibroblast populations cocultured with ECs, as efficient partners for vascular development in regenerative medicine strategies.

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Fibroblast heterogeneity: more than skin deep

Cited by 443 publications

References 127 publications

Lgr6 marks nail stem cells and is required for digit tip regeneration

Lgr6 marks nail stem cells and is required for digit tip regeneration

Origin of periendothelial cells in microvessels derived from human microvascular endothelial cells

Fibroblast-Endothelial Partners for Vascularization Strategies in Tissue Engineering

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