Modified Stem Cells Found to Ease Skin Scarring in Scleroderma Mice
Cells were pretreated to have more stable and reproducible effects
Treatment with modified mesenchymal stem cells (MSCs) — which can differentiate into a variety of cell types — alleviated the signs of skin scarring, or fibrosis, in a scleroderma mouse model, a study showed.
These MSCs, a type of adult stem cell that can modulate immune responses and suppress inflammation, were pretreated to have more stable and reproducible therapeutic effects, according to researchers.
In the lab, the modified MSCs worked by selectively reducing the recruitment of disease-causing immune macrophage cells to sites of inflammation. In other words, “the accumulation of macrophages was significantly decreased by MSC treatment,” the team wrote.
“This finding may help to improve MSC-based clinical treatments for SSc patients,” they added.
The mouse study, “Mesenchymal stem cells alleviate systemic sclerosis by inhibiting the recruitment of pathogenic macrophages,” was published in the journal Cell Death Discovery.
Fewer signs of skin scarring post-treatment
Scleroderma is an autoimmune disease marked by inflammation and fibrosis. In localized scleroderma, the skin and/or underlying muscle tissue is mainly affected, whereas in systemic scleroderma, also known as SSc, the disease can affect both skin and internal organs.
MSC transplant represents a potential treatment for people with SSc. These adult stem cells can become bone, muscle, or fat cells, but also are potent regulators of immune responses. Early research evaluating MSCs in systemic scleroderma indicated that treatment with these stem cells can improve quality of life through less pain and fatigue, better mobility, and easier breathing.
Studies have suggested that the type and level of inflammation can influence the therapeutic effects of MSCs. It is thought this may occur because the cells themselves are regulated by certain inflammatory signals that may be present at the site of inflammation.
Researchers in China recently worked to create MSCs with more stable and reproducible therapeutic effects by pre-treating them with two immune signaling proteins: interferon and TNF-alpha (MSC-IT). Now, the team tested the impact and underlying mechanism of these augmented MSCs in a mouse model of SSc.
After inducing SSc-like disease with the chemical BLM, mice were treated by MSC-IT via intravenous (into-the-vein) injection on days seven, 14, and 21; the animals were then examined on day 30.
MSC-IT treatment was found to significantly ease skin thickness and collagen deposits compared with untreated controls. Collagen is the main protein component of scar tissue.
Markers for fibrosis also were significantly reduced after MSC-IT treatment.
“Collectively, these results indicate that MSCs-IT are capable of mitigating the development of skin fibrosis during SSc,” the researchers wrote.
Experiments investigating how MSCs-IT reduced SSc symptoms found treatment lowered the number of immune macrophages and T-cells but did not affect neutrophils or antibody-producing B-cells. Further tests suggested that macrophages, not T-cells, were the main drivers of disease in SSc mice.
After depleting macrophages, skin thickness and collagen deposits decreased, “confirming the profibrotic role of macrophages in SSc,” the researchers noted. Importantly, they noted, MSC-IT treatment had no effect in macrophage-depleted SSc mice, indicating that “MSCs-IT alleviate BLM-induced SSc by acting on macrophages.”
The researchers then discovered that MSCs-IT did not affect fully mature macrophages but rather still-forming, immature macrophages, particularly those producing the protein receptor CCR2. The binding of the signaling protein CCL2 to its CCR2 receptor plays a role in recruiting macrophage precursor cells, called monocytes, to sites of inflammation.
The function of CCR2 on macrophages in SSc was confirmed by its pharmacological inhibition, which led to significantly decreased skin thickness and collagen deposits. Consistently, MSC-IT treatment had no effect in SSc mice after CCR2 inhibition. Additional experiments showed CCL2 was found at high levels in fibrotic skin but was significantly decreased after treatment.
Lastly, the team co-cultured MSCs-IT with mouse skin-derived fibroblasts, the connective tissue cells that secrete excess collagen in SSc scarring, or macrophages in the presence of BLM. The activity of the Ccl2 gene in fibroblasts and macrophages increased with BLM but was suppressed by MSCs-IT treatment, as was the level of CCL2 protein.
“Our results demonstrate that MSCs-IT reduce the accumulation of macrophages by inhibiting the generation of CCL2 from fibroblasts and macrophages, thus alleviating BLM-induced SSc,” the team wrote.
“This study provides insight into the mechanisms underlying MSC efficacies in autoimmune diseases,” they concluded.