Further notes about the morphostasis concept – split files

(47) Fibrotic repair.

It has been an ongoing puzzle to me as to why the repair of so much human tissue–damage leads to fibrosis. This reaches a zenith of intensity in burns. I have long suspected that it is a "panic driven" response. I now wonder if I have had some insight into this. It was an expeditious exchange on a Researchgate discussion forum that focused my attention on a recent article in the EMBO jornal . In an earlier response, Andrey Luchnik had asserted that wounds never heal from stem cells; he insisted that this was always from fibroblasts. "Always" is a alerting word in science and particularly bio-medicine. You can bet your bottom dollar that you are missing something (eg, cartilage never repairs/regenerates; it might not be good at it but we would all be seriously arthritic by our teens is this was absolutely true). So, armed with this paper on cancer (below) and wounding in zebrafish, it occurred to me that the inflammatory response is looking around for cells that show promise for regeneration. Where there is a struggle for dominance in some ecological arena, it is important to assert a clonal population dominance. The early stimulation of a suitable cell proliferation can help assert this dominance in the altered ecosystem of the wound. Suitable cells probably display at least some degree of stemness (less committed differentiation). In panic, neutrophils (the cells identified in the papers above) will choose the most available; these include fibroblasts and other mesenchymal stem cell related populations. These may have varyious degrees of differentiation. As this EMBO paper shows, they will also stimulate appropriately mutated, pre-cancerous cells. (A recent study shows just how common these pre-cancerous cells are .) With less panic, the best source, the dedicated tissue stem cell niches, could be enrolled into a scarless regeneration. Our bowels are well equipped to – scarlessly – replenish the intestinal epithelium. So, by stimulating fibroblasts in panic, we are probably forfeiting the opportunity for faultless repairs (which various observations indicate are possible). A number of stem cell niches are well recognised; the basal layer of the epidermis, the base of the hair follicle, intestinal crypts, at least a proportion of blood vessel pericytes and other niches in many other organs.

The other point worth making is that the immune system (morphostatic system) delivers a differential intensity of aggression to sites where inflammation is accelerated. It is preferentially skewed to aggression near unusual epitopes that were previously associated with damage. Now, although self tissue are differentially resistent to such accelerated attack, when the provocation is severe (perhaps equivalent to panic driven) then self cells are far from immune to the aggressive inflammatory milieu and this means that regeneration may be equally "under attack". It may be that this "out of balance" aggression to healthy self cells is responsible for the ensuing fibrotic scarring.