hMSCs Show Potential in Treating Chronic Lung Infections
Human mesenchymal stem cells (hMSCs) effectively treated infections caused by non-tuberculous mycobacteria in cell-based tests and a mouse model of cystic fibrosis (CF), a study revealed.
Although this strategy may help treat those infections in people with CF and other lung conditions, the findings show the treatment’s effectiveness depends on the donor source of hMSCs.
“Future studies are planned to evaluate unique hMSC fingerprints associated with antimicrobial potency,” the scientists wrote.
The study, “Donor‐defined mesenchymal stem cell antimicrobial potency against nontuberculous mycobacterium,” was published in the journal STEM CELLS Translational Medicine.
Mycobacterium avium and Mycobacterium intracellulare are two types of bacteria known as non-tuberculous mycobacteria (NTM). These bacteria occur naturally in the environment and are harmless to most people.
However, in people with lung conditions such as CF, bronchiectasis, and chronic obstructive pulmonary disease (COPD), as well as older people, NTMs can cause infection and often require extended treatment with antibiotics, which can lead to toxic side effects and eventual relapse.
“NTM infections can be very difficult to resolve,” Tracey Bonfield, PhD, the study’s lead author, said in a press release. “Treatment typically requires taking multiple antibiotics, often for years. Patients who suffer from chronic NTM infection not only deal with the consequences of the disease but also the toxicity, as well as inefficiency and side effects of the antibiotics used to treat it.”
To find better treatments for NTM infection, Bonfield and her team at Case Western Reserve University in Ohio focused on hMSCs, which can become a variety of cell types.
Studies have shown that hMSCs have anti-microbial, anti‐inflammatory, and anti-scarring properties resulting in improved antibiotic effectiveness, thereby decreasing the dose required to eliminate bacteria.
“They are dynamic storehouses of anti-microbial activity,” added Bonfield. “They are unique in their capacity to respond to infection by secreting multiple bioactive factors, contributing to the host environment. That gives hMSCs a clinical advantage over traditional pharmaceuticals.”
As M. avium and M. intracellulare — which form the so-called mycobacterium avium complex (MAC) — are slow‐growing bacteria, making it challenging to study sustained NTM infections, Bonfield’s team developed new models of M. avium and M. intracellulare lung infections.
“In the earlier studies, we had developed an innovative protocol in which M. avium and M. intracellulare can be evaluated over the course of a week instead of the typical four to six weeks,” said Bonfield.
Here, her team used the new modeling system to evaluate the potential of hMSCs to treat NTM infections.
First, in 24-hour cell-based tests, hMSCs significantly decreased the growth of MAC and trended toward a significant reduction in M. intracellulare. hMSC supernatants — the liquid that contains products secreted by these cells — also decreased growth in all conditions, but were significantly effective only in MAC.
Supernatants from 12 different hMSC donors were then cultured with MAC, M. intracellulare, and M. avium and tested over 24, 48, and 72 hours. Results showed the ability to decrease MAC growth varied based on hMSC preparation, with some supernatants killing most MAC, while others showed a lower capacity.
This variable effectiveness among different donor hMSC supernatants was also shown in M. intracellulare and M. avium separately.
“This suggested to us that it is essential to identify the appropriate hMSC donor and subsequent preparation for disease-specific applications,” said Bonfield.
hMSCs then were cultured with MAC, M. avium, or M. intracellulare with or without the addition of the antibiotic gentamicin. Although the antibiotic-enhancing capacity of hMSCs was higher against MAC and M. avium more than against M. intracellulare, the results varied across different donor preparations. In some, the potency was not sustainable.
Next, to test hMSCs in vivo, the most effective hMSC donor cells were used to treat normal, and CF model mice infected 24 hours earlier with either M. intracellulare or M. avium.
“We did this by embedding NTMs into beads of a polysaccharide [large molecules of simple sugars] extracted from seaweed called agarose and then injecting them into mice with CF,” Bonfield said. “The beads degrade gradually, releasing the NTM into the mice and thus extending the time of infection and inflammatory response. This modeling system has been very efficient in generating acute and chronic scenarios of infection in all of our models.”
Treatment of mice modeling CF with hMSCs resulted in significantly decreased growth of both M. intracellulare and M. avium in the lungs compared with CF mice not treated with hMSCs at day seven. hMSC treatment also attenuated weight loss and improved a score of overall health in infected CF mice.
Finally, to understand why some hMSC preparations were more potent than others, the team treated either free M. intracellulare or M. intracellulare embedded onto agarose beads with hMSCs and followed the gene activity profiles of immune signaling proteins (cytokines) that are known to contribute to NTM infections.
When they evaluated each hMSC preparation individually, the scientists found significant differences in overall response whether the M. intracellulare was free or embedded, which suggested that “the hMSC cytokine gene expression [activity] signature may be able to define anti‐NTM potency if gene expression profiles predict therapeutic functionality,” they wrote.
“Every donor hMSC preparation has a unique profile in terms of how the cells respond to pathogens, which likely translates into their successful potency and how the patient responds to hMSC treatment,” Bonfield said.” Focusing on hMSC response to NTMs and efficiency of in vitro [in the lab] and in vivo anti-NTM activity provides direction for identifying the optimal hMSC signature for anti-NTM therapy. Data gained from our study begins to define this unique hMSC fingerprint.”
According to Anthony Atala, MD, director of the Wake Forest Institute for Regenerative Medicine, who is also the editor-in-chief of STEM CELLS Translational Medicine, “the potential to use human mesenchymal stem cells to treat difficult lung infections is promising.”
“This study shows the ability of using optimal donors to obtain maximum treatment success,” he added.