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Irradiation-induced Damage to Human Skin-derived Stem Cells Inhibits Wound Healing

Review of “Mesenchymal Stromal Cells Isolated from Irradiated Human Skin Have Diminished Capacity for Proliferation, Differentiation, Colony Formation, and Paracrine Stimulation” from STEM CELLS Translational Medicine by Stuart P. Atkinson

While ionizing radiation represents an effective treatment for many solid tumors, this therapeutic approach suffers from unwanted side-effects, including the inhibition of wound healing through unknown mechanisms [1]. One hypothesis suggests that irradiation affects dermal stem cells, such as skin-derived mesenchymal stem cells (SMSCs), leading to persistent depletion and altered function [2]; however, in vitro studies have provided inconclusive results perhaps due to the failure to fully recapitulate the complex microenvironment of irradiated human skin [3, 4]. Furthermore, the field suffers from a lack of in vivo studies on irradiated SMSCs.

In a new STEM CELLS Translational Medicine article, researchers led by Alex K. Wong (University of Southern California, USA) hope to make a significant advance in this area by evaluating how ionizing radiation affects SMSCs isolated from human skin irradiated in situ, as occurs as part of neoadjuvant or adjuvant treatment for solid tumors [5]. Encouragingly, the results from this new study suggest that irradiation-induced in situ damage to SMSCs plays a critical role in the pathogenesis of slow or non-healing radiation wounds.

Johnson et al. compared cells isolated from severely irradiated and non-irradiated tissue samples taken patients undergoing reconstructive surgery, discovering that irradiated SMSCs displayed a range of similar alterations when compared to non-irradiated SMSCs regardless of the donor. These included an altered gene expression profile with significant differential expression of genes associated with skin physiology and wound healing, including DACT1, FMN1, and IL32. 

Furthermore, irradiated SMSCs displayed lower levels of characteristic marker expression, a disorganized cytoskeletal architecture, a disordered morphology, and enlarged nuclei, and exhibited functional defects with regards to their proliferative, differentiative, and colony-forming capabilities. Additionally, conditioned medium taken from cultures of irradiated SMSCs stimulated fibroblast migration to a lesser extent than conditioned medium from non-irradiated SMSCs, suggesting altered paracrine signaling. However, the study failed to see any effect of irradiated SMSC conditioned medium on endothelial cell proliferation and migration

Overall, this new study provides fresh insight into radiotherapy-associated side-effects in the skin, the largest organ in the human body, and establishes a potential mechanism for the appearance of non-healing wounds. Specifically, the authors hope to employ their gene expression data to identify therapeutic targets, such as the DACT1 Wnt signaling pathway inhibitor, that became 2.2‐fold upregulated in irradiated SMSCs. 

For more on the unwanted side-effects or irradiation on skin-derived stem cells and the development of novel strategies for non-healing wounds, stay tuned to the Stem Cells Portal!

References

  1. Dormand E-L, Banwell PE, and Goodacre TEE, Radiotherapy and wound healing. International Wound Journal 2005;2:112-127.
  2. Ahmed EA, Agay D, Schrock G, et al., Persistent DNA Damage after High Dose In Vivo Gamma Exposure of Minipig Skin. PLOS ONE 2012;7:e39521.
  3. Chen M-F, Lin C-T, Chen W-C, et al., The sensitivity of human mesenchymal stem cells to ionizing radiation. International Journal of Radiation Oncology • Biology • Physics 2006;66:244-253.
  4. Li J, Kwong DLW, and Chan GCF, The effects of various irradiation doses on the growth and differentiation of marrow-derived human mesenchymal stromal cells. Pediatric Transplantation 2007;11:379-387.
  5. Johnson MB, Niknam-Bienia S, Soundararajan V, et al., Mesenchymal Stromal Cells Isolated from Irradiated Human Skin Have Diminished Capacity for Proliferation, Differentiation, Colony Formation, and Paracrine Stimulation. STEM CELLS Translational Medicine 2019;8:925-934.