Modified fibroblasts, most commonly called myofibroblasts or activated fibroblasts, originate from multiple cell types depending on the tissue and type of injury involved. The primary source in most organs is the population of resident fibroblasts already living in that tissue, which transform into a more aggressive, scar-producing state when triggered by injury, inflammation, or disease. But resident fibroblasts are far from the only source. Cells lining blood vessels, epithelial cells, bone marrow cells, and even fat-storing cells in the liver can all give rise to modified fibroblasts under the right conditions.
Resident Fibroblasts: The Main Source
In most tissues, the largest pool of modified fibroblasts comes from ordinary fibroblasts that were already present before any injury occurred. These resident cells sit quietly in connective tissue, helping maintain the structural framework of organs. When tissue is damaged or placed under mechanical stress, chemical signals activate them into a modified state. In the heart, for example, resident cardiac fibroblasts are the primary source of myofibroblasts following a heart attack or in response to high blood pressure. Once activated, they produce large amounts of collagen and contractile proteins, essentially shifting from maintenance mode into an aggressive repair and scarring mode.
This transformation isn’t random. The most powerful trigger is a signaling molecule called TGF-beta, which acts through a specific internal pathway (the Smad3 pathway) to switch on genes that define the modified fibroblast identity. Experiments in mice lacking this pathway showed dramatically fewer myofibroblasts after lung injury, confirming its central role. Other triggers include angiotensin II (a molecule involved in blood pressure regulation) and increased physical tension on the tissue itself, such as what happens when a heart chamber stretches under pressure overload.
Tissue-Specific Sources Vary Widely
While resident fibroblasts are the default answer, certain organs rely on specialized local cells as the dominant source of modified fibroblasts. The differences are striking.
In the liver, the major sources are hepatic stellate cells and portal fibroblasts. Together, these two cell types account for over 95% of myofibroblasts in mouse models of liver fibrosis. Stellate cells are specialized cells that normally store vitamin A in the liver’s tiny blood vessel walls. They are, in fact, a type of pericyte, which are cells that wrap around small blood vessels. When the liver is injured by toxins or chronic disease, stellate cells alone can generate more than 87% of the myofibroblasts present. In bile duct injuries specifically, portal fibroblasts take the lead, contributing over 70% of myofibroblasts in the early stages.
In the kidney, pericytes have been identified as the major source of scar-producing myofibroblasts. This makes the kidney similar to the liver in that the cells wrapping around blood vessels, rather than fibroblasts sitting in connective tissue, are the primary culprits in fibrosis.
Epithelial and Endothelial Cells Can Convert Too
One of the more surprising sources of modified fibroblasts is epithelial cells, which are the cells lining the surfaces of organs and tubes throughout the body. Through a process called epithelial-mesenchymal transition (EMT), these cells lose their surface-lining characteristics and take on the properties of fibroblasts. In kidney fibrosis, lineage-tracing experiments in mice showed that roughly 30% of fibroblasts originated from the kidney’s tubular epithelial cells through EMT. Studies in 133 human patients with kidney fibrosis confirmed this process was occurring in a substantial number of cases.
Endothelial cells, which line the inside of blood vessels, can undergo a similar conversion. In mouse kidney fibrosis, about 35% of fibroblasts were found to derive from endothelial cells through what’s called endothelial-mesenchymal transition (EndMT). A study of patients with Crohn’s disease also demonstrated EMT occurring in fibrotic areas of the colon, showing this isn’t limited to the kidney.
Bone Marrow Sends Circulating Precursors
Not all modified fibroblasts come from cells already in the affected organ. The bone marrow produces circulating cells called fibrocytes, which travel through the bloodstream and can settle into injured tissues, where they differentiate into active fibroblasts. Fibrocytes represent a transitional state between circulating immune cells (monocytes) and tissue-resident fibroblasts.
The contribution of bone marrow-derived cells varies enormously by organ. In a mouse model of lung fibrosis, bone marrow-derived cells accounted for 80% of collagen-producing cells in the injured lung. In heart fibrosis after a coronary artery blockage, one study found that 57% of myofibroblasts were bone marrow-derived, while another found a more modest 24%. In the skin, bone marrow-derived cells made up only about 5% of collagen-producing cells during dermal fibrosis. The liver showed a similarly small contribution of 5 to 10%. And in one kidney fibrosis model, bone marrow-derived cells were vanishingly rare: just 1 in every 1,000 collagen-producing cells.
These wide-ranging numbers reflect both genuine biological differences between organs and differences in experimental methods. But the overall pattern is clear: bone marrow contribution matters most in the lungs and heart, and least in the kidneys, liver, and skin.
Cancer Creates Its Own Modified Fibroblasts
Tumors actively recruit and modify fibroblasts to support their growth, creating what are called cancer-associated fibroblasts (CAFs). In pancreatic cancer, CAFs commonly derive from three sources: resident fibroblasts already in the pancreas, pancreatic stellate cells (similar to the liver’s stellate cells), and mesenchymal stem cells that infiltrate the tumor from elsewhere in the body. These CAFs express distinctive surface proteins, including fibroblast activation protein-alpha (FAP) and alpha-smooth muscle actin, which distinguish them from normal, resting fibroblasts.
CAFs are not passive bystanders. They remodel the tissue around the tumor, create a supportive scaffold for cancer growth, and can influence how the immune system responds to the tumor. Understanding their origins has become a major focus in cancer research because disrupting the supply of CAFs could potentially slow tumor progression.
Lab-Engineered Fibroblasts From Stem Cells
Modified fibroblasts can also be created in the laboratory from human pluripotent stem cells, including both embryonic stem cells and induced pluripotent stem cells (iPSCs, which are adult cells reprogrammed back to a stem-like state). Researchers have developed protocols that use a specific growth factor called BMP4 along with defined culture conditions to guide stem cells through a directed differentiation into functional fibroblasts. These lab-derived fibroblasts can activate blood vessel growth both in cell culture and in living animals, making them useful for studying tissue repair and for potential regenerative medicine applications.
Why Multiple Sources Matter
The fact that modified fibroblasts arise from so many different cell types explains why fibrosis is so difficult to treat. Blocking one source, say resident fibroblasts, still leaves epithelial cells, endothelial cells, pericytes, and bone marrow-derived cells capable of generating new myofibroblasts. It also means that the mix of modified fibroblasts in any given disease is heterogeneous. Two myofibroblasts sitting side by side in a fibrotic kidney may have completely different cellular origins and may respond differently to treatment. This diversity is now recognized as a central challenge in developing anti-fibrotic therapies, and it is driving efforts to identify not just how many modified fibroblasts are present, but exactly where each one came from.