Scarring is an unfortunate fact of mammalian life, both following injury and throughout inner organs in old age, when the processes of regeneration and tissue maintenance run awry. Wound healing, or indeed any form of regeneration, is enormously complex. It is a dance of signals and actions carried out between numerous cell populations: various stem cells and progenitor cells; immune cells; somatic cells. These processes are similar at the high level in different tissues, but the details vary. It is far from completely mapped by the research community, as is true of most of cellular metabolism, particularly when multiple cell types are coordinating with one another.
Today's research is a good illustration of the complexities of regenerative biochemistry. When focusing down on even one class of cell in one tissue, fibroblasts in the skin, a wide variety of phenotypes and activities is revealed. Some of these apparently similar cells have arrived from far away in the body, and have very different roles from their peers of a similar type. If the mechanisms of scarring can be more carefully mapped in this way, there is perhaps the potential to reduce or prevent scars from forming. That would be a powerful technology, and probably more so for the ability to ameliorate some of the downstream damage of aging in organs rather than allowing better healing of injuries.
Skin injuries activate rapid wound repair, which often culminates with the formation of scars. Unlike normal skin, scars are devoid of hair follicles and fat cells, and creating new hair and fat is necessary for regenerating an equivalent of normal skin. In 2017 researchers identified that adult mice can naturally regenerate nearly normal-looking skin when new hair follicles and fat cells form in healing wounds. New fat cells regenerate from myofibroblasts, a type of wound fibroblast that was previously not thought to be capable of converting into other cell types. This discovery brought renewed attention to wound fibroblasts as attractive targets for anti-scarring therapies. In the current study, the research team sought to further characterize wound fibroblasts and determine if they're all the same and equally capable of regenerating new fat cells.
"We saw that wound fibroblasts are surprisingly very diverse and that there are as many as twelve different cell sub-types. We understand their molecular signatures and are beginning to learn about their unique biology. For example, we already know that distinct fibroblast sub-types 'prefer' only certain parts of the wound. This suggests that they play specific roles in different locations within the wound, and possibly at different times during the repair process. Molecular profiling of wound fibroblasts strongly suggests that as many as 13% of them at some point in their past were blood cells that converted into collagen-producing fibroblasts, but kept residual blood-specific genes still turned on."
"What is truly novel about our observation is that these fibroblast-making blood cells, which are called myeloid cells, can reprogram into new fat cells. In essence, we observed that for wounds to achieve scar-less regeneration, the body must mobilize multiple cellular resources, which includes remotely circulating blood progenitors." Because myeloid cells can be fairly easy to harvest and enrich using existing techniques, the new findings open the exciting possibility that the skin's healing ability can be enhanced via delivery of regeneration-competent blood-derived progenitors to the site of the wound.
Traditionally, adult mammals are considered to have limited regenerative abilities and scarring is thought to be the default repair response. The notable exceptions to this rule are digit tip regeneration after amputation and neogenesis of hair follicles and fat in the center of large excisional wounds. Intriguingly, lineage studies reveal important differences in the regenerative strategies between these two systems. Epithelial and mesenchymal structures in the digit tip regenerate from several types of fate-restricted progenitors and no multipotent progenitors or lineage reprogramming events are observed. In contrast, large skin wounds demonstrate broadened lineage plasticity. Although progeny of preexisting hair-fated bulge stem cells migrate into wound epidermis, they do not partake in hair follicle neogenesis. Instead, new hair follicles regenerate from non-bulge epithelial stem cells, among other sources. Fat neogenesis is driven by lineage reprogramming of non-adipogenic wound myofibroblasts. Dermal papilla neogenesis also likely relies on myofibroblast reprogramming strategy.
Are all wound myofibroblasts identical or heterogeneous in terms of their origin, properties, and morphogenetic competence? Here, we studied fibroblast heterogeneity in the mouse model for wound-induced regeneration at 12 days post-wounding when wound re-epithelialization is completed and preceding hair follicle neogenesis. We show that wound fibroblasts can be broadly classified into two major populations on the basis of their transcription factor signatures and PDGF receptor expression patterns. Prominent additional heterogeneity exists within both populations.
Bone-marrow-derived progenitors, including myeloid cells, endothelial progenitors, and circulating mesenchymal stem cells can contribute new stromal cells toward injured tissues in various organs. In skin, studies document bone marrow giving rise to fibroblasts at the injury sites. Our data from large excisional wounds shows that the contribution from myeloid cells to wound fibroblasts is small yet significant, between 6% and 11.3%, depending on the assessment method. We also showed that at least a portion of these cells can convert into de novo adipocytes around neogenic hair follicles.