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RESEARCH Open AccessCellular re- and de-programming bymicroenvironmental memory: why short TGF-β1pulses can have long effectsAriel Bing-Shi Tan 1,2,3 , Sebastian Kress 2,4 , Leticia Castro 5 , Allan Sheppard 5 and Michael Raghunath 2,3,6*AbstractBackground: Fibrosis poses a substantial setback in regenerative medicine. Histopathologically, fibrosis is anexcessive accumulation of collagen affected by myofibroblasts and this can occur in any tissue that is exposed tochronic injury or insult. Transforming growth factor (TGF)-β1, a crucial mediator of fibrosis, drives differentiation offibroblasts into myofibroblasts. These cells exhibit α-smooth muscle actin (α-SMA) and synthesize high amounts ofcollagen I, the major extracellular matrix (ECM) component of fibrosis. While hormones stimulate cells in a pulsatilemanner, little is known about cellular response kinetics upon growth factor impact. We therefore studied the effectsof short TGF-β1 pulses in terms of the induction and maintenance of the myofibroblast phenotype.Results: Twenty-four hours after a single 30 min TGF-β1 pulse, transcription of fibrogenic genes was upregulated,but subsided 7 days later. In parallel, collagen I secretion rate and α-SMA presence were elevated for 7 days. Asecond pulse 24 h later extended the duration of effects to 14 days. We could not establish epigenetic changes onfibrogenic target genes to explain the long-lasting effects. However, ECM deposited under singly pulsed TGF-β1was able to induce myofibroblast features in previously untreated fibroblasts. Dependent on the age of the ECM(1 day versus 7 days’ formation time), this property was diminished. Vice versa, myofibroblasts were cultured onfibroblast ECM and cells observed to express reduced (in comparison with myofibroblasts) levels of collagen I.Conclusions: We demonstrated that short TGF-β1 pulses can exert long-lasting effects on fibroblasts by changingtheir microenvironment, thus leaving an imprint and creating a reciprocal feed-back loop. Therefore, the ECM mightact as mid-term memory for pathobiochemical events. We would expect this microenvironmental memory to bedependent on matrix turnover and, as such, to be erasable. Our findings contribute to the current understanding offibroblast induction and maintenance, and have bearing on the development of antifibrotic drugs.Keywords: Fibrosis, Transforming growth factor-beta 1, Extracellular matrix, Memory, Pulses, Phenotype, Kinetics,CytokineBackgroundTissue repair is a physiological response to tissue dam-age. It starts with cell infiltration and inflammation atthe site of the lesion, progresses with the formation ofextracellular matrix (ECM) and ends with its remodel-ing, leaving a localized scar. When this response is trig-gered repeatedly or perpetuated, fibrosis ensues. Theworldwide clinical burden of fibrosis is substantial withat least 5 million cases of idiopathic lung fibrosis [1],and 170 million people with chronic hepatitis C atrisk for liver cirrhosis [2]. Fibrosis around implantscan effectively sequester them from surrounding tis-sue and impede their function [3-6]. Amongst vari-ous cytokines implicated in fibrosis, transforminggrowth factor-β1 (TGF-β1) is the most notorious. Itfacilitates the differentiation of fibroblasts, hepaticstellate cells [7], fibrocytes [8], and epithelial cells[9] into myofibroblasts, the drivers of collagen de-position and tissue contraction. After fulfilling theirinitial repair task myofibroblasts undergo apoptosis.* Correspondence: bierm@nus.edu.sg2 NUS Tissue Engineering Programme, Life Science Institute, NationalUniversity of Singapore, 28 Medical Drive, Singapore 1174563 Department of Bioengineering, Faculty of Engineering, National Universityof Singapore, 9 Engineering Drive 1, Singapore 117576Full list of author information is available at the end of the article© 2013 Tan et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.Tan et al. Fibrogenesis & Tissue Repair 2013, 6:12http://www.fibrogenesis.com/content/6/1/12