Stromal-Derived Factor-1 (SDF-1/CXCL12) and Skin Wound Healing Research at the Intersection Between Regenerative...

The history of stromal-derived factor-1 (SDF-1), alias CXCL12, started serendipitously and relatively late in the cytokine cDNA cloning era (1975-2000) and evolved at the biological level from progenitor cell-specific chemokine in the bone marrow to multifunctional cytokine with growth factor-like and tissue-regenerative activities. This evolution was parallelled by the integration of SDF-1/CXCL12 within the protein families of chemokines, cytokines and cell growth-promoting recombinant products having the potential for clinical applications. Here, we use this central position of CXCL12 as small signaling protein as an example for future developments in regenerative medicine. We provide context about SDF-1 biology within the field of skin wound healing research and how this compares with studies of other cytokines and growth factors. We also discuss whether SDF-1 formulations may be exemplary for other cytokines used for tissue regeneration. Normal skin wound healing is fraught with delays and complications in patients with specific underlying diseases, such as diabetes, hypertension and other elderly-related comorbidities, skin infections and accidental physical insults. Except for platelet-derived growth factor (PDGF), many cytokines, including vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), have failed so far in clinical studies of skin wound healing. This is in part due to the fact that (i) the biology of tissue regeneration is complex and insufficiently studied, (ii) in vitro approaches hardly mimic in vivo situations and (iii) commonly used animal models of acute and chronic wounding do not perfectly match human skin wound regeneration. A review of critical cells and molecules in normal skin and their actions in wounded tissue and a balanced comparison of the recent literature are preambles for progress in wound repair. We define advantages and limitations of recent approaches and appeal for more research. In particular, the possibilities of cellular immunomodulation mediated by endogenous and exogenous SDF-1/CXCL12 as a key molecule for skin regeneration are reviewed. Furthermore, biomaterials and scaffolds for the delivery and use of cytokines in precision medicine and aspects of their biofabrication are outlined with SDF-1 as an example. Finally, we indicate how applications of dermatological SDF-1 formulations for skin wound healing may be tailored for applications in other acute and chronic inflammatory conditions and regenerative medicine. Thereby, SDF-1/CXCL12 is placed at the crossroads between recombinant products, cytokines, chemokines and growth factors and occupies a central position between regenerative biology and medicine.