The “myofibroblast” that is omnipresent in pathology and key to the EMT concepts does not actually exist, since normal fibroblasts contain stress fibril organelles (SMA bundles with dense bodies) variably detected by TEM and IHC: Conclusions by a diagnostic pathologist with decades of ultrastructural experience

Abstract

The so-called “enigmatic” unique “myofibroblast” has been erroneously substituted for virtually all things fibroblastic in soft tissue pathology and believed to be the ultimate fibrogenic cell. It is also internationally considered to be the mesenchymal cell in un-proven post-natal EMT, EMT organ/tissue fibrosis, and the assumption that EMT/MET is key to carcinoma/adenocarcinoma invasion and metastasis. However, no such cell exists, having been mistaken for our normal ubiquitous fibrogenic fibroblasts that contain peripheral bundles of actin (SMA) with dense bodies, i.e. stress fibril (SF) organelles variably detectable by TEM and SMA IHC, depending on the degree of activation. The only detectable features distinguishing what are erroneously believed to be two unique fibrogenic spindle cells are the SF. Is the variable detection of SF/SMA in fibroblastic and non-fibroblastic lesions significant? Carcinosarcomas are not bi-phasic malignancies or proof of EMT/MET. What does it mean that the fibroblasts of so-called “carcinoma-associated fibroblasts (CAF)” are not “myofibroblasts”? The true myofibroblast is the ultrastructurally and functionally unique, terminally-differentiated, pathognomonic cell of physiologic wound-healing, which unfortunately has been confused with the activated fibroblast. This study fails to demonstrate any ultrastructural evidence that either normal epithelial (EMT) or carcinoma/adenocarcinoma cells can undergo reversible transition into mesenchymal cells (EMT/MET) under any circumstances. The SF/SMA-positive fibrogenic cell in organ/tissue fibrosis is the genetically up-regulated, activated fibroblast, which has no relationship to EMT. Are any of the innumerable biochemical factors/elements considered to be associated with this non-existent cell and its related processes related to the activated fibroblast? The conclusions are based on review of every electron micrograph taken during a 40-year career in diagnostic and research ultrastructural pathology, and by confirming that the published TEM figures of so-called “myofibroblasts”, are actually of fibroblasts.

• Fibroblast
• SMA
• soft tissue pathology
• stress fibrils
• TEM
• wound-healing myofibroblast

Acknowledgements

My deepest gratitude to Drs. Ronald Spark and Stuart Cameron for their steadfast support; and for 40 years of the best technologists, one could ever hope for.

Notes

*Dedication: Dedicated to the memory of Herschel Sidransky, MD, a cherished mentor and chairman, of the Pathology Department at the George Washington University Medical Center during most of my career, and prior to “money medicine” enveloping academic medicine, and the progressive elimination of diagnostic electron microscopy.