Hacking Nature: Using Stem Cells to Combat Major Opioid Issues

3-D printing. Virtual reality. Artificial intelligence. Self-driving cars. Robotic surgery. Gene editing. Higgs boson. The list goes on. These recent breakthroughs are becoming household words (and items), and they are a testament to the rapid expansion of our society’s technological capabilities. In the world of medical research, however, this paradigm has recently shifted towards exploring natural biological systems rather than focusing on the typical research areas of medical devices and drug development. These biological systems can potentially be rewired to address seemingly hopeless medical challenges. One example of this strategy is incorporating stem cells into treatment approaches by repurposing their capabilities to target specific diseases. Stem cells mainly function to form the organs of the body during embryonic development (embryonic stem cells) and maintain them throughout adulthood (adult stem cells). These functions are achieved through two powerful abilities that are specific to stem cells: the ability to indefinitely replicate and to differentiate into other cell types. Medical researchers are constantly learning more about these two unique capabilities, aiming to take advantage of them en route to making stem cell-based therapies a reality. Animal studies and on-going human clinical trials have made great strides towards developing stem cell-based therapies for diseases such as stroke, spinal cord injury, Parkinson's disease, and diabetes [1]. In fact, a few stem cell-based treatment approaches have even been approved for clinical use, such as hematopoietic stem cell transplantation for sickle cell disease [2].

 Image Credit:  Public domain

Image Credit: Public domain

 

Despite all of the promising stem cell research progress, there are still millions of patients afflicted with illnesses for which the medical field has no answers. These medical challenges are ideal candidates for stem cell research, as their respective treatment approaches are clearly ineffective. One prime example of this is the current opioid epidemic, which causes over 100 U.S. deaths daily and nearly $80 billion per year in national economic burden [3]. While opioid abuse patients experience many complications, two significant issues facing these patients are opioid tolerance (OT) and opioid-induced hyperalgesia (OIH) (Figure 1). OT is described as reduced sensitivity to a drug, thus requiring higher doses to achieve similar effects and putting opioid users at risk of overdose. OIH is a condition in which the user experiences a heightened amount of pain in response to external stimuli. This change is likely caused by opioids having off-target effects on certain neurotransmitter pathways, increasing the probability of a pain response [4]. Moreover, both OT and OIH seem to involve abnormal behavior of immune cells within the nervous system.

  Figure 1. Comparing opioid tolerance (OT) & opioid-induced hyperalgesia (OIH).  Image Credit:  Kaleab Tessema

Figure 1. Comparing opioid tolerance (OT) & opioid-induced hyperalgesia (OIH). Image Credit: Kaleab Tessema

 

Current approaches for treating OT and OIH are only moderately effective, mainly because the strategies do not directly target OT and OIH, but rather the symptoms of each. As pain is the primary symptom in both cases, the currently approved treatment approach focuses primarily on pain management [4, 5]. Since OT reduces the patient’s sensitivity to opioids, the doses must continuously be increased to achieve effective pain management. Furthermore, since these higher doses will either initiate or worsen OIH, the patient is forced to increase their opioid doses even more. As a result, the patient becomes increasingly dependent on opioids for day-to-day life. This treatment approach is unproductive; thus, improving the strategies for OT and OIH treatment is of critical importance, especially in the context of the current opioid abuse epidemic.

 

Considering recent progress in developing stem cell-based therapies, would it be possible to use stem cells to address these significant issues tied to opioid use?

 

Dr. Jianguo Cheng’s research group at Cleveland Clinic has been investigating a stem cell-based approach to address both OT and OIH, with promising preliminary success [6]. Their approach uses a specific type of stem cells called mesenchymal stem cells (MSCs). MSCs are responsible for developing most of the body’s structural framework, including bones, cartilage, fat, and muscles. Recent studies have shown that MSCs can also target the immune system within certain organs, mainly those within the nervous system, by secreting specific molecules that alter the behavior of immune cells. Since OT and OIH both involve abnormal immune system activation in the nervous system, Dr. Cheng’s group hypothesized that MSCs may potentially be useful as a treatment approach [6].

 

To investigate this hypothesis, the researchers took MSCs from rat bone marrow and injected them directly into the bloodstream and spinal fluid of rats and mice. To test both the preventive and therapeutic potential of MSC transplantation, the researchers separated animals into two groups. One group received morphine injections before MSC transplantation, and the other group received MSCs before morphine. Remarkably, both experimental groups showed improvement after MSC transplantation, suggesting a potential benefit for using MSCs to both prevent and treat OT and OIH. In terms of prevention, injecting MSCs one day or seven days before daily morphine injection led to a significant reduction in OT and OIH. In terms of treatment, MSC injection 14 days after starting morphine injection was effective in reducing the OT and OIH that had developed in the animals. Finally, routine evaluations showed that the MSC injections did not alter any important bodily functions, suggesting that the injections were safe to perform in these animals. While the mechanism of how MSCs reduce symptoms in these animals is unclear, some of the findings suggest that MSCs are indeed targeting immune reactions in the nervous system, which is in line with the original motivation for exploring MSC-based therapy [6]. Although this study could lead to future human clinical trials, it is essential to recognize that findings from animal studies are extremely preliminary in terms of clinical applicability.

  Experimental outline of MSC-based treatment and prevention of OT & OIH in mice and rats. Image credit:  Victoria Sun

Experimental outline of MSC-based treatment and prevention of OT & OIH in mice and rats. Image credit: Victoria Sun

 

This finding, in addition to others of its kind, exemplifies the versatility and potential utility of stem cells as therapeutic tools. Biomedical research is moving towards repurposing stem cells for medical use, highlighting an exciting transition from synthetic medicinal agents and drug discovery to more patient-based and cellular approaches, which is rapidly expanding our ability to develop effective and efficient medical care for a broad range of diseases.

 

 

Kaleab Tessema

Staff Writer, Signal to Noise Magazine

MD/PhD Candidate, Molecular Biology Interdepartmental Doctoral Program, UCLA

 

 

References:

[1] Trounson, A., McDonald, C. Stem Cell Therapies in Clinical Trials: Progress and Challenges. Cell Stem Cell 17(1), 11-22 (2015).

[2] Levasseur, D. N., Ryan, T. M., Pawlik, K. M., Townes, T. M. Correction of a mouse model of sickle cell disease: lentiviral/antisickling β-globin gene transduction of unmobilized, purified hematopoietic stem cells. Blood 102(13), 4312-4319 (2003).

[3] National Institute on Drug Abuse. Opioid Overdose Crisis. https://www.drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis (2018).

[4] Bottemiller, S. Opioid-Induced Hyperalgesia: An Emerging Treatment Challenge. US Pharm 37(5), HS-2-HS-7 (2012).

[5] Adesoye, A., Duncan, N. Acute Pain Management in Patients With Opioid Tolerance. US Pharm 42(3), 28-32 (2017).

[6] Hua, Z. et al. Mesenchymal Stem Cells Reversed Morphine Tolerance and Opioid-induced Hyperalgesia. Scientific Reports 6, 32096 (2016).