Preface

Fibroblasts are vital structural cells of the human body with core roles in tissue homeostasis and disease. While primarily recognised as producers of extracellular matrix and central effectors in wound healing, using them as a feeder layer in cell culturing sheds some understanding on their nurturing roles for other cell types. Recent years have brought remarkable advances in molecular and functional characterisation of fibroblasts, decoding their organ and sub-tissular niche specificity, anatomical sub-specialisation, reactivity, heterogeneity and plasticity across the human body in health and disease. This knowledge substantially changed our conventional view about fibroblast roles in human disease. In 2021, fibroblasts are being widely recognised for their active contribution to chronicity, recurrence, progression and therapeutic resistance against many human pathologies, including chronic inflammatory and systemic autoimmune diseases and cancer.

This book provides essential insights into shared and unique characteristics of fibroblasts and mesenchymal stem cells across the body and their crosstalk with the innate and adaptive immune systems, other tissue-resident cells and cancer cells. The book explains the roles of fibroblasts and mesenchymal stem cells in shaping tissue microenvironments and structural immunity and discusses the recent discoveries about their pathogenic actions in tissue remodelling, repair, inflammation, angiogenesis or lymphangiogenesis, particularly in autoimmune diseases and cancer. The first two chapters uncover the general principles of fibroblast and mesenchymal stem cell biology and pathobiology, followed by a focused insight into shared and unique characteristics of exocrine, vascular, synovial and salivary gland fibroblasts in the following four chapters.

Chapter 1, *Organ- and Site-Specific HOX Gene Expression in Stromal Cells*, delves into the embryonically imprinted positional memory of tissue-resident fibroblasts with a principal focus on the coding and non-coding genes in the HOX clusters. Professor Ospelt and colleagues discuss the contribution of epigenetic mechanisms to the location-specific fibroblast imprinting across the human body and furthermore, review the implication of site-specific fibroblast memories for organ-specific tropism of human pathologies, such as arthritis and cancer—the seed and soil principle. In Chapter 2, *Mesenchymal Stem/Stromal Cells and Fibroblasts: Their Roles in Tissue Injury and Regeneration, and Age-Related Degeneration*, Assistant Professor Zupan introduces and aligns the characteristics of tissue-resident fibroblasts and tissue-derived mesenchymal stem cells in homeostatic and pathological conditions, including injury and age-related tissue degeneration. Both cell types crucially control and contribute to the regeneration of skin, ligaments, joints, bone and other tissues and have potent immunomodulatory roles, enabling a successful cessation of the inflammatory process. Boosting the complementary roles of mesenchymal stem cells and fibroblasts could be therapeutically exploited for tissue regeneration. Chapter 3, *The Role of Fibroblasts in Atherosclerosis Progression*, offers further insights into the associations between stem cells and fibroblasts from a perspective of an arterial wall. Professor Šemrl and

colleagues discuss a challenging delineation between stem cells and fibroblasts at the adventitia/media niche and summarise the heterogeneity of vessel wall fibroblasts. Adventitial fibroblasts, populating healthy vessel walls, characteristically migrate to and invade the media and intima of the injured or stress vessels. These cells then drive neointima formation, can transdifferentiate into extracellular matrix-depositing myofibroblasts, promote adventitial neovascularisation and regulate immune cell infiltration, thus crucially contributing to vascular pathologies, such as atherosclerosis and pulmonary artery hypertension. In Chapter 4, *Heterogeneity of Fibroblasts in Healthy and Diseased Kidneys*, the book's focus steers from the vascular towards kidney fibroblasts and their pronounced regional and functional heterogeneity. A small subset of corticomedullary fibroblasts that express erythropoietin and control erythropoiesis exemplifies this regional specialisation of kidney fibroblasts. Professor Yanagita and colleagues re-examine the dual roles of kidney fibroblasts, particularly their contribution to renal tubule regeneration contrasted by their pathogenic roles in kidney fibrosis and inflammation, and discuss fibroblast roles in the formation of the tertiary lymphoid structures in chronic kidney diseases and rheumatoid arthritis, and Sjögren's syndrome as part of the succeeding chapter. In Chapter 5, *Fibroblast-Like Synovial Cell Subsets in Rheumatoid Arthritis*, Associate Professor Kragstrup and colleagues present the recent discoveries about the diversity of fibroblast-like synoviocytes/synovial fibroblasts in rheumatoid arthritis based on single-cell RNA-sequencing studies. Synovial fibroblast functions in the initiation and persistence of synovial inflammation and joint destruction are illuminated. The authors review the evidence about the roles of lining CD55+ synovial fibroblasts in cartilage and bone destruction, depict the enrichment of the proinflammatory sublining THY1+ synovial fibroblasts in rheumatoid arthritis and propose potential fibroblast markers for the development of targeted treatments. Moving from the autoimmune diseases of the synovial joints to the autoimmune diseases of the exocrine glands, Chapter 6, *Fibroblasts in Sjögren's Syndrome*, emphasises the inflammatory, immunomodulatory and regenerative functions of salivary gland fibroblasts in Sjögren's syndrome, a chronic inflammatory autoimmune disease of the exocrine glands. The chapter describes specific fibroblast subsets that drive the formation of tertiary lymphoid structures associated with disease severity and risk of lymphoma development. Dr. Klein wraps up the chapter with the recently introduced concept of an inflammatory fibroblast phenotype shared across many chronic immune-mediated inflammatory diseases. This concept excellently repercusses the overall book's goal of utilising expanding fibroblast knowledge to develop the pathology-based patient classification and propose novel therapies beyond disease boundaries.

> **Mojca Frank Bertoncelj** BioMed X Institute, Heidelberg, Germany

**Katja Lakota** Department of Rheumatology, University Medical Centre (UCM) Ljubljana, Ljubljana, Slovenia

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