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Evidence for the Nonmuscle Nature of The" Myofibroblast" of Granulation Tissue and Hypertropic Scar. an Immunofluorescence Study

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Evidence for the Nonmuscle Nature of The American Journal of Pathology, Vol. 130, No. 2, February 1988 Copyright i American Association of Pathologists Evidencefor the Nonmuscle Nature ofthe "Myofibroblast" ofGranulation Tissue and Hypertropic Scar An Immunofluorescence Study ROBERT J. EDDY, BSc, JANE A. PETRO, MD, From the Department ofAnatomy, the Department ofSurgery, and JAMES J. TOMASEK, PhD Division ofPlastic and Reconstructive Surgery, and the Department of Orthopaedic Surgery, New York Medical College, Valhalla, New York Contraction is an important phenomenon in wound cell-matrix attachment in smooth muscle and non- repair and hypertrophic scarring. Studies indicate that muscle cells, respectively. Myofibroblasts can be iden- wound contraction involves a specialized cell known as tified by their intense staining of actin bundles with the myofibroblast, which has morphologic character- either anti-actin antibody or NBD-phallacidin. Myofi- istics of both smooth muscle and fibroblastic cells. In broblasts in all tissues stained for nonmuscle but not order to better characterize the myofibroblast, the au- smooth muscle myosin. In addition, nonmuscle myo- thors have examined its cytoskeleton and surrounding sin was localized as intracellular fibrils, which suggests extracellular matrix (ECM) in human burn granula- their similarity to stress fibers in cultured fibroblasts. tion tissue, human hypertrophic scar, and rat granula- The ECM around myofibroblasts stains intensely for tion tissue by indirect immunofluorescence. Primary fibronectin but lacks laminin, which suggests that a antibodies used in this study were directed against 1) true basal lamina is not present. The immunocytoche- smooth muscle myosin and 2) nonmuscle myosin, mical findings suggest that the myofibroblast is a spe- components ofthe cytoskeleton in smooth muscle and cialized nonmuscle type of cell, not a smooth muscle nonmuscle cells, respectively, and 3) laminin and 4) cell. (Am J Pathol 1988, 130:252-260) fibronectin, extracellular glycoproteins mediating TISSUE CONTRACTION is an important phenom- microfilaments, which resemble the myofibrils of enon in the repairing dermis of open wounds and in smooth muscle. The surface ofthese cells was covered hypertrophic scarring. Initially, the shortening ofcol- by an interrupted amorphous layer of extracellular lagen fibers in the extracellular matrix was thought to material similar to the basal lamina surrounding be responsible; however, this was challenged by the smooth muscle cells. Because these cells showed mor- demonstration that wounds made in scorbutic ani- phologic characteristics of both fibroblasts and mals contract independent ofcollagen production.' A smooth muscle cells, Gabbiani and associates2 termed cellular mechanism for contraction has been pro- them "myofibroblasts." The presence ofthese cells in posed by Gabbiani and co-workers2'3 after their dis- covery of a morphologically distinct cell found in ac- tively granulating wounds. Upon ultrastructural Supported by funds provided by the Department ofSur- examination, this cell type appeared to have charac- gery, Division of Plastic Surgery, New York Medical Col- lege, Valhalla, New York teristics ofboth fibroblasts and smooth muscle cells.2'3 Accepted for publication September 1, 1987. In addition to having extensive rough endoplasmic Address reprint requests to Dr. James J. Tomasek, De- reticulum and Golgi apparatus characteristic offibro- partment of Anatomy, Basic Sciences Building, New York blasts, these cells contained large bundles of actin Medical College, Valhalla, NY 10595. 252 Vol. 130 * No. 2 NONMUSCLE NATURE OF THE MYOFIBROBLAST 253 actively contracting granulation tissue and hypertro- by a matrix rich in fibronectin but lacking laminin. phic scar,4 as well as other contractile tissues such as Therefore, our immunofluorescence studies ofthe cy- the palmar fascia during Dupuytren's disease,5 and toskeleton and extracellular matrix of myofibro- their morphologic characteristics have led to the pro- blasts, in human and rat granulation tissue and hy- posal that the myofibroblast is the cellular agent re- pertrophic scar, suggest that this cell has sponsible for tissue contraction.3 characteristics similar to fibroblasts, rather than After numerous morphologic studies, uncertainty smooth muscle cells. still exists as to whether the myofibroblast more closely resembles the fibroblast or the smooth muscle cell. Therefore, we examined the cytoskeleton and Materials and Methods extracellular matrix of myofibroblasts from human Tissue burn granulation tissue, rat granulation tissue, and human hypertrophic scar, with immunologic probes Granulation tissue was taken from 2 patients un- for proteins characteristic of either fibroblasts or dergoing debridement ofthe burn wound. Hypertro- smooth muscle cells. Two aspects of the myofibro- phic scar tissue was taken from 1 patient undergoing blast were studied: 1) the type of myosin in the cyto- scar contracture release. Granulation tissue was also skeleton and 2) the macromolecules in the extracellu- taken from 4 female Sprague-Dawley rats each lar matrix. The selection ofthese cellularcomponents weighing approximately 250 g. Open wounds were was based on their presumed role in the generation made on rats which were anesthetized with an intra- and transmission of contractile force. peritoneal injection ofsodium pentabarbitol in phos- Myosin is a cytoskeletal protein that interacts with phate-buffered saline. There backs were shaved and actin to generate contractile force in both muscle and depilated (Nair, Carter Wallace, Inc., Cranbury, NJ), nonmuscle cells.6 The myosin associated with smooth and an antiseptic solution (Podiodine, Larson Labo- muscle cells is distinct from that found in nonmuscle ratories, Inc., Erie, Pa) was applied.A single 2 X 2-cm cells.7 To determine which species ofmyosin is asso- full-thickness excision was made on the dorsum of ciated with myofibroblasts of human burn granula- each animal and the wound left open. Two weeks tion tissue, rat granulation tissue, and hypertrophic after wounding, the animals were sacrificed and the scar, we employed antibodies that can distinguish be- granulation tissue excised. All the tissues were cut into tween smooth muscle myosin and nonmuscle myosin 2-3-cu mm pieces and prepared for histologic and in conjunction with indirect immunofluorescence.8 immunocytochemical staining by fixation in 4% Smooth muscle cells are surrounded by a highly paraformaldehyde in 0.1 mol/1 phosphate buffer, pH organized layer of extracellular material called the 7.4, for 20 minutes at room temperature. The tissue basal lamina.9 This structure functions in maintain- was infiltrated with 30% sucrose, mounted in OCT ing intercellular connections and transmitting compound (Lab-Tek Products, Miles Laboratories, changes in cell shape, such as contraction, across a Naperville, Ill), and rapidly frozen by immersion in tissue fabric. Basal laminae contain the glycoprotein liquid nitrogen. Cryostat sections (4-6,u) were thaw- laminin,'0 which binds the cell to the surrounding mounted onto gelatin-coated glass slides. Type IV collagen layer." In contrast, fibroblasts have no basal lamina and therefore lack laminin.'0 A dif- ferent glycoprotein, fibronectin, attaches fibroblasts Antibodies to their surrounding stromal (Types I and III) colla- The anti-nonmuscle myosin antibody was a gift gen.'2 Previous studies of myofibroblasts in human from Dr. Keigi Fujiwara (National Cardiovascular wound granulation tissue,'3 experimental granula- Research Institute, Suita-Shi, Osaka, Japan). It is a tion tissue,'4 and hypertrophic scar'5 have demon- rabbit antiserum against human platelet myosin pre- strated fibronectin at the surface ofthese cells. How- pared as previously described.16 Previous studies with ever, the distribution of laminin in these tissues is this antibody have shown it to react with the myosin unknown. To determine the distribution of laminin ofnonmuscle cells, including fibroblasts and vascular with respect to fibronectin at the surface of myofi- endothelial cells, but not with the myosin of smooth broblasts in granulation tissue and hypertrophic scar, muscle cells.8 we employed antibodies specific for laminin or fibro- The anti-smooth muscle myosin antibody, also a nectin in conjunction with indirect immunofluores- gift from Dr. Keigi Fujiwara, is a rabbit antiserum cence. against human uterine myosin prepared as previously In this report, we demonstrate that myofibroblasts described.8 By double immunodiffusion, this anti- contain only nonmuscle myosin and are surrounded body formed a single precipitin line with extracts of 254 EDDY ET AL AJP * February 1988 human uterus but not with extracts of human plate- matrix antibodies were blocked with normal goat lets or cardiac or skeletal muscle. Immunofluores- serum diluted 1:10 in PBS for 30 minutes at room cence microscopy shows this antibody to stain all vis- temperature. Sections were then incubated with the ceral and vascular smooth muscle tested, but no other appropriate primary antibody for 30 minutes at room cell type, including epithelial, endothelial, and fibro- temperature, except for the anti-myosin antibodies, blastic cells as well as cardiac and skeletal muscle.8 which were incubated overnight at 4 C. Antibodies A monoclonal antibody raised against quail muscle were diluted in PBS (anti-actin antibody, 1: 500; anti- actin was a gift from Dr. Michael Payne (Department nonmuscle myosin and smooth muscle myosin anti- of Anatomy, New York
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