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Author

Martha L. Funderburgh

Other affiliations: Kansas State University
Bio: Martha L. Funderburgh is an academic researcher from University of Pittsburgh. The author has contributed to research in topics: Stromal cell & Keratan sulfate. The author has an hindex of 34, co-authored 57 publications receiving 3652 citations. Previous affiliations of Martha L. Funderburgh include Kansas State University.


Papers
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Journal ArticleDOI
TL;DR: The results demonstrate the presence of a population of cells in the human corneal stroma expressing stem cell markers and exhibiting multipotent differentiation potential, and appear to be the first human cells identified with keratocyte progenitor potential.
Abstract: Keratocytes of the corneal stroma secrete a specialized extracellular matrix essential for vision. These quiescent cells exhibit limited capacity for self-renewal and after cell division become fibroblastic, secreting nontransparent tissue. This study sought to identify progenitor cells for human keratocytes. Near the corneal limbus, stromal cells expressed ABCG2, a protein present in many adult stem cells. The ABCG2-expressing cell population was isolated as a side population (SP) by cell sorting after exposure to Hoechst 33342 dye. The SP cells exhibited clonal growth and continued to express ABCG2 and also PAX6, product of a homeobox gene not expressed in adult keratocytes. Cloned SP cells cultured in medium with fibroblast growth factor-2 lost ABCG2 and PAX6 expression and upregulated several molecular markers of keratocytes, including keratocan, aldehyde dehydrogenase 3A1, and keratan sulfate. Cloned corneal SP cells under chondrogenic conditions produced matrix staining with toluidine blue and expressed cartilage-specific markers: collagen II, cartilage oligomatrix protein, and aggrecan. Exposure of cloned SP cells to neurogenic culture medium upregulated mRNA and protein for glial fibrillary acidic protein, neurofilament protein, and beta-tubulin II. These results demonstrate the presence of a population of cells in the human corneal stroma expressing stem cell markers and exhibiting multipotent differentiation potential. These appear to be the first human cells identified with keratocyte progenitor potential. Further analysis of these cells will aid elucidation of molecular mechanisms of corneal development, differentiation, and wound healing. These cells may be a resource for bioengineering of corneal stroma and for cell-based therapeutics.

300 citations

Journal Article
TL;DR: In this paper, the ABCG2-expressing cells were identified as a side population (SP) by cell sorting after exposure to Hoechst 33342 dye and the SP cells exhibited clonal growth and continued to express ABCG 2 and also PAX6, product of a homeobox gene not expressed in adult keratocytes.
Abstract: Keratocytes of the corneal stroma secrete a specialized extracellular matrix essential for vision. These quiescent cells exhibit limited capacity for self-renewal and after cell division become fibroblastic, secreting nontransparent tissue. This study sought to identify progenitor cells for human keratocytes. Near the corneal limbus, stromal cells expressed ABCG2, a protein present in many adult stem cells. The ABCG2-expressing cell population was isolated as a side population (SP) by cell sorting after exposure to Hoechst 33342 dye. The SP cells exhibited clonal growth and continued to express ABCG2 and also PAX6, product of a homeobox gene not expressed in adult keratocytes. Cloned SP cells cultured in medium with fibroblast growth factor-2 lost ABCG2 and PAX6 expression and upregulated several molecular markers of keratocytes, including keratocan, aldehyde dehydrogenase 3A1, and keratan sulfate. Cloned corneal SP cells under chondrogenic conditions produced matrix staining with toluidine blue and expressed cartilage-specific markers: collagen II, cartilage oligomatrix protein, and aggrecan. Exposure of cloned SP cells to neurogenic culture medium upregulated mRNA and protein for glial fibrillary acidic protein, neurofilament protein, and beta-tubulin II. These results demonstrate the presence of a population of cells in the human corneal stroma expressing stem cell markers and exhibiting multipotent differentiation potential. These appear to be the first human cells identified with keratocyte progenitor potential. Further analysis of these cells will aid elucidation of molecular mechanisms of corneal development, differentiation, and wound healing. These cells may be a resource for bioengineering of corneal stroma and for cell-based therapeutics.

246 citations

Journal ArticleDOI
TL;DR: The qualitatively similar expression of glycosaminoglycans shared by fibroblasts and myofibroblast suggests a role for fibro Blasts in deposition of non-transparent fibrotic tissue in pathological corneas.

224 citations

Journal ArticleDOI
TL;DR: Funderburgh et al. as mentioned in this paper showed that the keratan sulfate-containing proteoglycans of bovine corneal stroma contain three unique core proteins designated 37A, 37B, and 25.

213 citations

Journal ArticleDOI
TL;DR: It is concluded that the full-length translation product of the gene producing osteoglycin is a corneal keratan sulfate proteoglycan, also present in many non-corneal tissues without keratan sulphate chains.

194 citations


Cited by
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Journal ArticleDOI
TL;DR: The proteoglycan superfamily now contains more than 30 full-time molecules that fulfill a variety of biological functions and additional roles, derived from studies of mutant animals, indicate that certain proteoglycans are essential to life whereas others might be redundant.
Abstract: The proteoglycan superfamily now contains more than 30 full-time molecules that fulfill a variety of biological functions. Proteoglycans act as tissue organizers, influence cell growth and the maturation of specialized tissues, play a role as biological filters and modulate growth-factor activities, regulate collagen fibrillogenesis and skin tensile strength, affect tumor cell growth and invasion, and influence corneal transparency and neurite outgrowth. Additional roles, derived from studies of mutant animals, indicate that certain proteoglycans are essential to life whereas others might be redundant. The review focuses on the most recent genetic and molecular biological studies of the matrix proteoglycans, broadly defined as proteoglycans secreted into the pericellular matrix. Special emphasis is placed on the molecular organization of the protein core, the utilization of protein modules, the gene structure and transcriptional control, and the functional roles of the various proteoglycans. When possible, proteoglycans have been grouped into distinct gene families and subfamilies offering a simplified nomenclature based on their protein core design. The structure-function relationship of some paradigmatic proteoglycans is discussed in depth and novel aspects of their biology are examined.

1,650 citations

Journal ArticleDOI
TL;DR: It is suggested that weakening the extracellular scaffold of adipocytes enables their stress-free expansion during states of positive energy balance, which is consequently associated with an improved inflammatory profile and implicating “adipose tissue fibrosis” as a hallmark of metabolically challenged adipocytes.
Abstract: Adipocytes are embedded in a unique extracellular matrix whose main function is to provide mechanical support, in addition to participating in a variety of signaling events. During adipose tissue expansion, the extracellular matrix requires remodeling to accommodate adipocyte growth. Here, we demonstrate a general upregulation of several extracellular matrix components in adipose tissue in the diabetic state, therefore implicating "adipose tissue fibrosis" as a hallmark of metabolically challenged adipocytes. Collagen VI is a highly enriched extracellular matrix component of adipose tissue. The absence of collagen VI results in the uninhibited expansion of individual adipocytes and is paradoxically associated with substantial improvements in whole-body energy homeostasis, both with high-fat diet exposure and in the ob/ob background. Collectively, our data suggest that weakening the extracellular scaffold of adipocytes enables their stress-free expansion during states of positive energy balance, which is consequently associated with an improved inflammatory profile. Therefore, the disproportionate accumulation of extracellular matrix components in adipose tissue may not be merely an epiphenomenon of metabolically challenging conditions but may also directly contribute to a failure to expand adipose tissue mass during states of excess caloric intake.

875 citations

Journal ArticleDOI
TL;DR: The proposed nomenclature encompasses forty-three distinct proteoglycan-encoding genes and many alternatively-spliced variants and is based on three criteria: Cellular and subcellular location, overall gene/protein homology, and the utilization of specific protein modules within their respective protein cores.

856 citations

Journal ArticleDOI
TL;DR: A crucial role is established for lumican in the regulation of collagen assembly into fibrils in various connective tissues and the development of a highly organized collagenous matrix and corneal transparency.
Abstract: Lumican, a prototypic leucine-rich proteoglycan with keratan sulfate side chains, is a major component of the cornea, dermal, and muscle connective tissues. Mice homozygous for a null mutation in lumican display skin laxity and fragility resembling certain types of Ehlers-Danlos syndrome. In addition, the mutant mice develop bilateral corneal opacification. The underlying connective tissue defect in the homozygous mutants is deregulated growth of collagen fibrils with a significant proportion of abnormally thick collagen fibrils in the skin and cornea as indicated by transmission electron microscopy. A highly organized and regularly spaced collagen fibril matrix typical of the normal cornea is also missing in these mutant mice. This study establishes a crucial role for lumican in the regulation of collagen assembly into fibrils in various connective tissues. Most importantly, these results provide a definitive link between a necessity for lumican in the development of a highly organized collagenous matrix and corneal transparency.

698 citations

Journal ArticleDOI
TL;DR: The focus is on the “functional network” created by these molecules in tissues, on genetic evidence for their functional roles during ontogeny, and on their activities as modulators of complex pathological processes such as fibrosis and cancer growth.

667 citations