Home Neurological Disorders ALS Steering Stem Cells to Repair Sites Using Inflammo-Free Inflammo-Attraction

Steering Stem Cells to Repair Sites Using Inflammo-Free Inflammo-Attraction

0
Neural stem cells maturing into astrocytes (yellow). [Sanford Burnham Prebys Medical Discovery Institute]

Transplanted stem cells instigate healing only after they reach a repair site, or “pathologic niche.” To help transplanted stem cells find their way, scientists have considered exploiting a natural inflammo-attraction system. It guides stem cells to inflammatory signals emitted by damaged tissue. The system, however, has usually been deemed too hot, that is, too apt to worsen inflammation and harm the body.

If only it were possible to shed the “inflammo” part of inflammo-attraction. Then, therapeutic stem cells could be deployed like smart bombs—except that they’d provide more balm than blam.

The possibility has been investigated by scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP). In a recent study, they reported that they modified an inflammatory “homing” molecule to create a drug that enhances stem cell binding and minimizes inflammatory signaling. They assert that this drug, which is called SDV1a, can be injected anywhere to lure stem cells to a specific location without causing inflammation.

Details appeared online in the Proceedings of the National Academy of Sciences (PNAS), in an article titled, “Chemical mutagenesis of a GPCR ligand: Detoxifying ‘inflammo-attraction’ to direct therapeutic stem cell migration.” The article describes how SBP scientists, led by Evan Y. Snyder, MD, PhD, professor and director of the Center for Stem Cells and Regenerative Medicine at SBP, and the senior author of the current study, modified CXCL12—an inflammatory molecule which Snyder’s team previously discovered could guide healing stem cells to sites in need of repair—to create SDV1a.

Binding of CXCL12 to a neural stem cell receptor (NCR) called CXCR4 (a G protein-coupled receptor, or GPCR) triggers repair processes within the NCR. To avoid the inflammation that follows CXCL12–CXCR4 coupling, the scientists chemically “mutated” CXCL12, creating a CXCR4 agonist that contained a strong pure binding motif linked to a signaling motif devoid of sequences responsible for synthetic functions.

“Since inflammation can be dangerous, we modified CXCL12 by stripping away the risky bit and maximizing the good bit,” said Snyder. “Now we have a drug that draws stem cells to a region of pathology, but without creating or worsening unwanted inflammation.”

To demonstrate that the new drug could improve the efficacy of a stem cell treatment, the researchers implanted SDV1a and human neural stem cells into the brains of mice with a neurodegenerative disease called Sandhoff disease.

“[Our] synthetic dual-moiety CXCR4 agonist … elicited more extensive and persistent human NSC migration and distribution than did native CXCL12,” wrote the article’s authors. “[No] host inflammation or other adverse effects [were induced]; rather, there was predominantly reparative gene expression. When co-administered with transplanted human induced pluripotent stem cell–derived hNSCs in a mouse model of a prototypical neurodegenerative disease, the agonist enhanced migration, dissemination, and integration of donor-derived cells into the diseased cerebral cortex where their secreted cross-corrective enzyme mediated a therapeutic impact unachieved by cells alone.”

Essentially, this experiment showed SDV1a helped the human neural stem cells migrate and perform healing functions. Improvements included extended lifespan, delayed symptom onset, and preserved motor function. Besides avoiding the activation of inflammation, the guided stem cells were able to suppress any preexisting inflammation.

According to the study’s authors, their drug, a “designer” cytokine receptor-agonist peptide, illustrates how stem cell treatments can be controlled and optimized by exploiting fundamental stem cell properties such as inflammo-attraction. The general approach could improve stem cell therapies designed to treat such neurological disorders as spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS), and other neurodegenerative disorders. It could also be helpful for disorders in which initial inflammatory signals fade over time—such as chronic spinal cord injury or stroke—and conditions where the role of inflammation is not clearly understood. That is, stem cell therapies could be expanded to new conditions, such as heart disease or arthritis.

“The ability to instruct a stem cell where to go in the body or to a particular region of a given organ is the Holy Grail for regenerative medicine,” said Snyder. “Now, for the first time ever, we can direct a stem cell to a desired location and focus its therapeutic impact.”

The researchers have already begun testing SDV1a’s ability to improve stem cell therapy in a mouse model of ALS, also known as Lou Gehrig’s disease, which is caused by progressive loss of motor neurons in the brain. Previous studies conducted by Snyder’s team indicated that broadening the spread of neural stem cells helps more motor neurons survive—so the scientists are hopeful that strategic placement of SDV1a will expand the terrain covered by neuroprotective stem cells and help slow the onset and progressive of the disease.

“We are optimistic that this drug’s mechanism of action may potentially benefit a variety of neurodegenerative disorders, as well as non-neurological conditions such as heart disease, arthritis, and even brain cancer,” related Snyder. “Interestingly, because CXCL12 and its receptor are implicated in the cytokine storm that characterizes severe COVID-19, some of our insights into how to selectively inhibit inflammation without suppressing other normal processes may be useful in that arena as well.”