THE BIOLOGY OF SKIN REGENERATION: THE IMPORTANCE OF THE FIBROBLAST

Dr. Martine Baspeyras

Dr. Martine Baspeyras is a dermatologist specializing in dermatologic surgery, aesthetic dermatology, and cosmetic science. Based in Bordeaux since 1991, she is recognized as a longstanding figure in French aesthetic dermatology, combining clinical expertise, scientific engagement, and institutional leadership.

Having previously held clinical appointments at hospitals in Paris (Saint-Louis, Necker, and Henri-Mondor) and Bordeaux (Haut-Levêque and the Children’s Hospital), she has developed extensive expertise through a particularly comprehensive academic background encompassing aesthetic dermatology, cosmetic science, advanced cutaneous oncologic surgery, cutaneous oncology, cervicofacial surgical anatomy, chronobiology, and medical hypnosis.

Actively involved in scientific societies, she chairs the VIGILANCE ESTHÉTIQUE Group, a leading organization dedicated to monitoring and improving the safety of aesthetic dermatology procedures. She is also President of the French Society of Aesthetic Dermatology (SFED). Her work has helped establish structured approaches to the prevention, documentation, and analysis of complications associated with aesthetic procedures, making her a recognized authority on quality and safety in patient care.

A member of the French Society for Lasers in Dermatology, the French Society of Dermatology, the French Society of Dermatologic Surgery, and the American Academy of Dermatology, Dr. Baspeyras actively participates in expert groups focusing on cosmetic science, lasers, and safety monitoring in aesthetic practice.

The author of numerous scientific publications and presentations, she has also contributed to several phase III clinical trials, particularly in psoriasis and botulinum toxin. Her scientific work and commitment to the profession have established her as a recognized voice in aesthetic dermatology, both in France and internationally.

Regeneration is the biological capacity of living organisms, cells, tissues, or organs to reconstitute themselves following partial destruction, thereby replacing damaged structures.

Skin regeneration is a remarkably complex biological process that depends on the dynamic integration of biochemical, mechanical, and immunologic signals. Although modern therapeutic approaches often focus on growth factors, stem cells, or biomaterials, evidence accumulated over the past two decades points to one cell: the fibroblast, which has emerged as the central cellular regulator of dermal homeostasis.

Understanding skin regeneration therefore requires consideration of fibroblast biology, extracellular matrix dynamics, and the mechanisms of mechanotransduction that enable tissue to translate physical information into a biological response.

Discovered by Rudolf Virchow in 1858, the fibroblast is of mesenchymal origin. In 1985, Ernest Ziegler described its different morphologic forms, namely the fibroblast, fibrocyte, and myofibroblast, along with the importance of cellular tension in promoting neocollagenesis.

As the predominant cell type in the dermis, the fibroblast was long regarded as little more than a collagen-producing cell. Today, it is recognized as a sentinel cell capable of sensing changes in its environment, continuously remodeling the extracellular matrix, communicating with all cellular populations in the dermis and epidermis, and adapting its phenotype to the mechanical and biological stresses to which it is exposed.

Referring to “the fibroblast” is therefore an oversimplification. Single-cell transcriptomic technologies have demonstrated the existence of multiple fibroblast subpopulations with distinct genetic, metabolic, and functional signatures. Depending on their anatomic location, whether in the papillary dermis, reticular dermis, perivascular tissue, or follicular sheath, and their functional state, fibroblasts perform specific roles and exhibit different morphologic characteristics.

The fibroblast acts as an orchestrator, simultaneously performing several functions essential to dermal physiology. It continuously builds, maintains, and degrades its own environment. This dual capacity for synthesis and degradation is one of the fundamental principles of homeostasis.

Its synthetic activity encompasses the components of its dermal environment, including types I, III, V, and VI collagen, elastin, fibrillin microfibrils, fibronectin, tenascin, an extracellular matrix glycoprotein, proteoglycans, and glycosaminoglycans, particularly hyaluronic acid. It also produces numerous matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-9, and MMP-13), together with their physiologic inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). The precise balance between matrix synthesis and proteolysis directly determines the biomechanical properties of the dermis. Any disruption of this balance leads either to pathologic fibrosis or to the excessive degradation observed in skin aging.

Fibroblasts respond to external stimuli and perform diverse functions, including the secretion of proinflammatory factors, adipogenesis, and antigen presentation, revealing remarkable heterogeneity and plasticity. These findings establish fibroblasts as important contributors to the pathogenesis of skin diseases, challenging the traditional view of these cells as exclusively structural elements. Based on their diverse functions, fibroblasts are classified into six subtypes: proinflammatory fibroblasts, myofibroblasts, adipogenic fibroblasts, angiogenic fibroblasts, mesenchymal fibroblasts, and antigen-presenting fibroblasts.

The fibroblast communicates throughout its dermal and epidermal environment, including with keratinocytes. As a cellular source of inflammatory cytokines and chemokines, it promotes chronic tissue inflammation by recruiting leukocytes and exacerbating inflammatory lesions. Recent studies using histologic approaches and single-cell RNA sequencing in human skin diseases have identified fibroblast subpopulations with unexpected immunomodulatory transcriptomes, along with changes in immune cells, suggesting a potential role for these fibroblasts in the pathogenesis of inflammatory dermatoses.

Fibroblasts have considerable proliferative, differentiation, and migratory capacities. In response to harmful stimuli, they can differentiate into myofibroblasts and secrete extracellular matrix (ECM) components and cytokines to mitigate damage from external insults and restore skin function. Conversely, fibroblast dysfunction also contributes to skin diseases such as psoriasis and atopic dermatitis.

Keratinocytes secrete factors capable of modulating fibroblast activity. In turn, fibroblasts regulate keratinocyte proliferation, differentiation, and migration through the production of numerous mediators.

They also communicate with macrophages, mast cells, dendritic cells, T lymphocytes, endothelial cells, pericytes, and follicular stem cells. This communication relies on an extensive network of cytokines, chemokines, and growth factors (TGF-β, PDGF, VEGF, FGF, CTGF, and IGF-1), as well as extracellular vesicles and exosomes.

The fibroblast thus emerges as a central regulatory hub coordinating the full range of local biological responses.

Fibroblasts possess biomechanical properties, a characteristic shared by living organisms. Mechanical forces are necessary for cell survival, proliferation, division, contraction, and intracellular trafficking.

Mechanosensation is the fibroblast’s response to changes in its environment, whereas mechanotransduction is the transmission of this information through biochemical signals. Mechanical information is conveyed through the dynamics of the cellular actin cytoskeleton.

Following tissue injury, fibroblasts migrate and mediate healing through the different stages of inflammation and wound repair. They recruit and activate immune cells in response to cytokines, chemokines, and other inflammatory stimuli.

Mechanotransduction involves cells sensing the mechanical properties of the ECM through integrins and the actomyosin cytoskeleton. This is followed by mechanoregulation, involving ECM deposition, rearrangement, or removal to preserve overall tissue form and function.

The extracellular matrix is a dynamic network that provides mechanical and biochemical signals regulating cellular behavior. ECM stiffness strongly influences fibroblasts, particularly during inflammation and fibrosis. As the principal producers of ECM components, fibroblasts are highly sensitive to mechanical signals and play a central role in the interaction between ECM stiffness and inflammatory responses.

Mechanotransduction pathways involving integrins, focal adhesion kinase (FAK), Rho-associated kinase (ROCK), and Yes-associated protein (YAP) are central to these processes. These pathways convert mechanical signals into biochemical responses, regulating gene expression and cellular behavior in response to changes in ECM stiffness.

Cellular mechanotransduction, which converts environmental mechanical signals into biochemical signals, plays a crucial role in regulating fibroblast inflammatory responses. ECM stiffness is a key biophysical factor influencing fibroblast activation, proliferation, and cytokine secretion.

Altered ECM stiffness is associated with fibrosis, wound healing, and conditions such as chronic inflammation. Fibroblasts sense and respond to the mechanical properties of the ECM through integrin-mediated adhesion complexes and cytoskeletal remodeling. This triggers downstream signaling cascades, including the YAP/TAZ and TGF-β pathways, which modulate inflammatory gene and protein expression. Integrins and YAP illustrate the complexity of cellular mechanotransduction mechanisms linking mechanical stimuli to biochemical responses.

Under physiologic conditions, fibroblasts maintain tissue integrity by producing ECM components such as collagen and fibronectin. During inflammation, however, cytokines such as TGF-β and IL-1β activate fibroblasts, inducing a shift toward a proinflammatory state.

Integrins act as mechanoreceptors, transmitting mechanical signals from the ECM to intracellular signaling cascades and influencing the expression of genes associated with inflammation and fibrosis. More specifically, YAP activation in response to increased stiffness has been associated with increased expression of fibrosis markers and cytokines. ECM stiffness also influences the secretion of matrix metalloproteinases involved in ECM remodeling.

Tissue fibrosis is a pathologic condition characterized by excessive ECM deposition, resulting in increased tissue stiffness and impaired organ function. It affects numerous organ systems, including the heart, lungs, skin, intestines, and skeletal muscles.

Fibrosis is primarily driven by fibroblast activation and differentiation into myofibroblasts, which secrete profibrotic cytokines and contribute to ECM remodeling. The mechanical properties of the ECM, particularly its stiffness, play a crucial role in regulating fibroblast behavior, including activation, proliferation, and cytokine secretion through mechanotransduction pathways, thereby exacerbating fibrosis progression and inflammation.

What happens to fibroblasts with age?

Aged skin exhibits impaired epidermal barrier function, dermal thinning with an accumulation of senescent fibroblasts, and ECM alterations.

Compared with young skin, from individuals aged 18–29 years, the total number of fibroblasts is approximately 35% lower in aged skin, from individuals over 80 years of age. Meanwhile, the number of senescent fibroblasts increases with age, as demonstrated by a significant increase in p16INK4a-positive cells in the dermis of aged human skin. p16INK4a is a marker of cellular senescence that encodes a CDK4/6 inhibitor.

Senescent fibroblasts undergo proliferative arrest but remain viable because of their low propensity for apoptosis and inefficient clearance by the immune system. Their excessive accumulation contributes significantly to skin aging, as these cells exhibit a loss of cellular identity, increased secretion of senescence-associated secretory phenotype (SASP) factors, and disrupted ECM homeostasis.

Senescence spreads from cell to cell, perpetuating dermal aging. The SASP comprises a mixture of molecules released by senescent cells, including cytokines, matrix metalloproteinases, microRNAs, chemokines, growth factors, and small metabolites. These molecules exert immunoregulatory effects and influence the proliferation and motility of nonsenescent cells.

Proteins involved in ECM degradation (MMP-1, MMP-3, MMP-10, MMP-14, and others), as well as proinflammatory mediators such as interleukin-1 [symbol missing in the source], IL-8, IL-15, and interferon gamma (IFN-γ), have been identified in the SASP associated with skin aging.

SASP-associated MMPs directly cleave collagen fibrils and play an important role in ECM degradation during aging. Levels of MMPs, particularly MMP-1, MMP-2, and MMP-9, increase in the aging dermis. This increase is accompanied by a reduction in tissue inhibitors of metalloproteinases in aged skin, resulting in an MMP/TIMP imbalance and progressive collagen fragmentation.

TIMP-1 overexpression protects the ECM against degradation and loss of elasticity induced by chronic UVB exposure, whereas a TIMP-1-neutralizing antibody has the opposite effect. Fibroblasts in aged skin reduce their production of ECM, whose principal components include types I and III collagen. This process results primarily from reduced TGF signaling [symbol missing in the source].

The many functional profiles of fibroblasts, together with their plasticity and adaptation to their surroundings, make them key regulators of their environment. Fibroblasts are directly involved in tissue regeneration and the maintenance of skin homeostasis.

Fibroblasts in fibrotic skin exhibit increased activation and proliferation as a result of this stiffening. Mechanical signals from the stiffened ECM activate YAP signaling pathways, inducing profibrotic cytokine overexpression and promoting fibroblast activation. This creates a vicious cycle that perpetuates skin fibrosis.

The fibroblast is a fascinating cell that synthesizes and degrades, communicates with other cells, and has yet to reveal all its secrets. It should no longer be regarded as a simple effector cell, but as a central integrator of tissue regeneration.

References

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Yu GT, Ganier C, Allison DB, Tchkonia T, Khosla S, Kirkland JL, Lynch MD, Wyles SP. Mapping epidermal and dermal cellular senescence in human skin aging. Aging Cell. 2025 Jan;24(1).

Tiskratok W, Chuinsiri N, Limraksasin P, Kyawsoewin M, Jitprasertwong P. Extracellular Matrix Stiffness: Mechanotransduction and Mechanobiological Response-Driven Strategies for Biomedical Applications Targeting Fibroblast Inflammation. Polymers (Basel). 2025 Mar 20;17(6):822. doi: 10.3390/polym17060822. PMID: 40292716; PMCID: PMC11946729.

Zhang J, Yu H, Man MQ, Hu L. Aging in the dermis: Fibroblast senescence and its significance. Aging Cell. 2024 Feb;23(2):e14054.