Clumps of modified stem cells seen to ease skin, lung scarring in mice
Results of lab study make MSCs 'ideal candidate' for SSc therapy
Modifying mesenchymal stem cells (MSCs) — a type of stem cell found in various tissues and, in this case, taken from the umbilical cord of mice — and using clumps of them in a mouse model of systemic sclerosis (SSc) was found to ease signs of skin and lung fibrosis, or scarring, and to reduce inflammation in the animals.
In a laboratory study, a team of scientists in China found that treatment with these clumps, or aggregates, alleviated both fibrosis and inflammation in the mice.
“These results suggest that [aggregates of modified MSCs] are ideal candidates for SSc therapy and optimize the clinical utilization of MSCs,” the researchers wrote.
The study, “Engineered MSC Aggregates with E/N-Cadherin and IL-6 Preconditioning for the Treatment of Systemic Sclerosis,” was published in the journal Advanced Healthcare Materials.
SSc is an autoimmune disease characterized by inflammation and fibrosis in the skin and several internal organs, including the heart, lungs, and kidneys.
Investigating the therapeutic effects of MSCs in SSc
MSCs have been deemed promising candidates for treating autoimmune-related fibrosis, because they can regulate the immune system and inflammation. Emerging evidence suggests that exposing MSCs to disease-specific molecules may enhance their immunological properties and therapeutic effects in SSc.
Now, a research team from institutions in China further developed MSC aggregates that had been exposed to a human E/N-cadherin lab-made protein and to interleukin (IL)-6.
E- and N-cadherin are cellular adhesion molecules critical to maintaining the abilities of MSCs to self-renew and differentiate into various cell types. IL-6, meanwhile, acts as a proinflammatory and profibrotic molecule and is abnormally elevated in SSc patients. It can enhance the therapeutic efficacy of MSCs against inflammatory diseases.
Here, MSCs derived from the umbilical cord of mice were maintained on an E/N-cadherin modified surface and treated with IL-6 to form 3D aggregates. The scientists called these aggregates 3D-Cad/IL-6-MSCs, and compared their immunoregulatory and anti-inflammatory capabilities to those of nonmodified MSCs, which were used as controls.
Compared with the control MSCs, the modified aggregates were smaller: 72.2 versus 76 micrometers. According to the investigators, this indicates that the cellular connections become more compact when incorporating E/N-cadherin. Also, they expressed higher levels of cellular adhesion molecules, including E- and N-cadherin, and of molecules involved in the IL-6 signaling pathway.
Particularly, levels of the STAT1 protein — involved in the IL-6 pathway — were higher in modified MSC aggregates, indicating greater anti-inflammatory properties, the researchers noted.
“Overall, by preconditioning MSC aggregates with [human E/N-cadherin] and IL-6 synergistically, we developed novel MSC aggregates with more compact structures and increased expression of endogenous [produced by the body] cadherin and components of the classical IL-6 pathway,” the team wrote.
Further analysis revealed that 3D-modified MSCs had higher activity of genes related to suppressing inflammation and forming new blood vessels than control aggregates, the researchers noted.
Modified MSCs found more effective for reducing lung scarring
In a next step, the researchers grew stem cell aggregates with peripheral blood mononuclear cells, which include several types of immune cells.
The results demonstrated that modified MSCs more effectively reduced the levels of pro-inflammatory T-cells, while increasing the levels of regulatory T-cells that limit inflammatory responses.
When aggregates of modified MSCs were injected into mice, they remained detectable for five days, including in the lungs, unlike control stem cells, the scientists found.
Additionally, in a mouse model of fibrosis, 3D-Cad/IL6-MSC treatment was more effective at reducing skin inflammation and thickness, and at reducing excessive deposits of collagen, a main component of scar tissue. It also reduced the infiltration of inflammatory cells in the skin.
Future research will focus on clarifying the underlying mechanisms, optimizing safety, and facilitating clinical translation. … We expect that this will accelerate the transition of 3D-Cad/IL-6-MSCs from the laboratory bench to the patient’s bedside and bring benefits to SSc patients.
In the lungs — which are frequently affected in SSc — modified MSC aggregates more effectively reduced fibrosis and inflammatory cell infiltration. They also reduced bodywide inflammation, indicated by the levels of T-cells and inflammatory molecules.
“Future research will focus on clarifying the underlying mechanisms, optimizing safety, and facilitating clinical translation,” the researchers wrote. “We expect that this will accelerate the transition of 3D-Cad/IL-6-MSCs from the laboratory bench to the patient’s bedside and bring benefits to SSc patients.”
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