August 16, 2019
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Ionizing radiation may damage stem cells ‘critically involved in wound healing’

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Alex K. Wong
Alex K. Wong

In situ damage to skin-derived mesenchymal stem cells during neoadjuvant or adjuvant radiotherapy appeared to have a significant effect on the pathogenesis of slow or nonhealing radiation wounds, according to study findings published in Stem Cells Translational Medicine.

“Although effective in the treatment of solid tumors, radiotherapy produces a number of off-target effects in the overlying skin,” Alex K. Wong, MD, reconstructive surgeon in the division of plastic and reconstructive surgery at Keck School of Medicine of USC, and colleagues wrote. “These changes result in skin that responds poorly to wounding by trauma or surgery, predisposing to the development of chronic wounds.”

Current wound care regimens for patients treated with ionizing radiation for solid tumors have demonstrated limited effectiveness.

For this reason, Wong and colleagues sought to evaluate genome-wide differential expression between skin-derived mesenchymal stem cells (SMSCs) isolated from irradiated skin and SMSCs from nonirradiated skin.

Investigators found that SMSCs isolated from irradiated human skin showed a characteristic phenotype associated with substantial derangements of cellular function.

“Importantly, these radiated SMSCs exhibit both a significant impairment in capacity for differentiation and altered paracrine signaling, affecting cells known to be critically involved in wound healing,” the researchers wrote.

HemOnc Today spoke with Wong about what prompted this research, what he and colleagues found, and plans for subsequent research.

Question: What prompted this research?

Answer: As a reconstructive plastic surgeon, I see a lot of patients with solid tumors who are treated using a combination of modalities, including neoadjuvant chemotherapy, radiation or surgery followed by adjuvant radiation or chemotherapy. When surgeries involve a solid tumor, it often results in a disfiguring defect — there is a big void of tissue.

That is why, as a reconstructive surgeon, I get involved. When radiation is not used, the process is relatively simple —I can do flaps and grafts and they work with pretty high reliability. However, when a patient either has had radiation before tumor removal or needs to have radiation after surgery, it is a wild card in terms of how the soft tissue responds and heals.

It is well-established that radiation inhibits wound healing. For example, if a patient with soft tissue sarcoma had neoadjuvant radiation followed by surgery to remove the tumor, reconstruction would be challenging, because radiated skin behaves poorly — it is subject to infection, prone to fluid collections and sometimes does not heal. To address this problem, I remove all radiated skin, but this can be quite a large area because radiation oncologists generally are very conservative and radiate a huge field to minimize the risk for local recurrence. For example, if a patient has cancer of the right breast, the entire chest wall is typically radiated. This is a huge field and we simply cannot remove all of the radiated tissue. For this reason, I wanted to study radiated skin to try and get a better idea of why it does not heal correctly, and then use that information to help develop new therapeutics.

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Q: How did you conduct the study and what did you find ?

A: In general, the solution for fixing the radiated tissue is to remove most of it and reconstruct with tissue that has not been radiated. This gave us an opportunity to biopsy the radiated skin in the operating room and save it for laboratory analysis. Because I replace the radiated skin with normal skin from elsewhere on the body, I was able to take a small portion of that skin and create a prospective catalog or database to keep track of the paired patient samples. Directly comparing samples from the same individual helped minimize background noise one might have in the study of clinical samples.

We confirmed that our skin biopsy samples had radiation injury by histology. This established that radiation injures all components of the skin and anything beneath it, including the terminally differentiated keratinocytes, fibroblasts, fat cells and vascular endothelial cells. We were interested in finding out if the progenitor in the skin is affected by radiation. Each tissue has its own local niche of stem cells, and SMSCs that are limited to the skin help in maintaining skin homeostasis. They are stem-like progenitors that are different from differentiated cells. To determine whether or not SMSCs were equally injured by radiation, we took the radiated and normal skin samples from the same patients and isolated the SMSCs using standardized techniques. The first thing we wanted to know was whether it was possible to isolate this kind of cell type from radiation damaged skin. Once we confirmed that was possible, we looked at the skin under the microscope and found that the stem cells from the radiated tissue had significant morphologic differences. We tested them and assessed whether they could proliferate normally. We pushed the SMSCs toward the fat and bone lineages and found that both could be differentiated. This verified their ‘stem-ness.’ We also found that the stem cells secreting less growth factors, which normally serve to support fibroblast function, are important. Lastly, we performed RNA sequencing analysis on the SMSCs from radiated and normal skin samples and found that they had distinctly different patterns of gene expression.

Q: Do you have plans for additional research?

A: Stem cells in the skin are potentially viable targets for modulation. If we can fix what happened to the stem cells and repair them, the skin may have a better chance of repairing itself. We can now go to the source of what regenerates the skin and at fix it as opposed to trying to fix all the differentiated fibroblasts, endothelial cells and keratinocytes. We believe that by improving the health of the stem cells, that they can regenerate healthy cells to repair this tissue. This could minimize the need for surgery, which is expensive and risky. However, there is more to do. We have a couple of targets that we revealed in RNA sequencing, but this needs to be functionally tested. Thus, confirmation and testing the efficacy of our putative targets constitutes the plan for the immediate future.

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Q: Is there anything else that you would like to mention?

A: I hope that our study increases awareness of post-radiation abnormalities and highlights the fact that they are a critical problem. My oncology colleagues, whether they are medical oncologists or radiation oncologists, do their very best to treat the cancer, but the people who survive are left with deformities from adjuvant treatment. I am not saying that we should not radiate people, because it works very well to help eradicate cancer cells, but heightened awareness of its aftereffects is a good thing for anyone involved in the management of patients with cancer. – by Jennifer Southall

Reference:

Johnson MB, et al. Stem Cells Transl Med. 2019;doi:10.1002/sctm.18-0112.

For more information:

Alex K. Wong, MD, can be reached at Keck School of Medicine of USC, 1510 San Pablo St., Suite 415, Los Angeles, CA 90033; email: alex.wong@med.usc.edu.

Disclosure: Wong reports no relevant financial disclosures. The study was funded in part by a grant from the Robert E. and May R. Wright Foundation.