Stem cell research is a field that is filled to the brim with promise and possibilities. Its premise is simple: stem cells, which are a population of undifferentiated cells, can differentiate into different types of cells according to need. In other words, they have the regenerative properties to replace defective tissue, bone, and cartilage.
Stem cells carry within them 3 important features: an ability to self-renew and proliferate extensively, clonality, and the ability to differentiate into various cell types.
“Stem cells are an important tool for understanding both the organogenesis and the continuous regenerative capacity of the body,” Kolios and Moodley wrote in Respiration. “There is ongoing research and development that gives us great optimism about regenerative medicine.”
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The use of stem cells as a therapeutic strategy has made it almost synonymous with modern medicine itself. The reasons for this are twofold: first, they are heavily used in clinical research (in which direct testing on human subjects is deemed too risky); second, their wide range of applications make them appealing to both medical and biological sciences. Stem cells help us understand human development and organogenesis, which in turn helps us to develop new and safe therapies.
Stem cells are like a “blank check” that can be used across a wide range of scenarios; also, we have barely scratched the surface of what they can do. If we dare to cast the nets of our imagination far and wide, we can envision how stem cells can potentially be used to treat every degenerative disease that exists, just as how they have already been used to research diseases such as pulmonary fibrosis, cirrhosis, Crohn’s disease, and heart failure.
A quick note on the ethical controversies surrounding stem cell research. For individuals who believe that life begins at conception, the very idea of stem cell research is a nonstarter, since it often requires the destruction of embryos. Although most Western countries have adopted a more liberal approach to this subject, it remains a hot-button issue here in the United States.
Stopping the Progression of DMD
Filippelli and Chang conducted a study on the use of muscle stem cells for the treatment of Duchenne muscular dystrophy (DMD). As published in Cell Tissue Organs, they explored the advantages of restoring endogenous muscle stem cell function in degenerative muscle as a treatment strategy to halt the progression of DMD.
Let us review the nature of DMD, and why it is a suitable candidate for stem cell experimentation. DMD is a chronic, progressive disease in which muscle wasting occurs. Patients, sooner or later, will find it difficult to ambulate to the point where they may be unable to climb stairs or experience frequent falls.
Read more about DMD etiology
Duan and colleagues highlighted a few key consequences of the deficiency in the dystrophin protein that occurs with DMD:
- Sarcolemma weakening. In DMD, sarcolemmas are highly susceptible to contraction damage.
- Functional ischemia. In DMD, protective vasodilatory mechanisms are compromised, possibly leading to muscular ischemic damage.
- Free-radical damage. DMD muscles produce a significantly higher amount of free radicals compared to normal muscles.
- Cytosolic calcium overloading. The resting cytosolic calcium concentration in DMD muscles is significantly higher than that in healthy muscles.
- Consequences of muscle damage. Autophagy is impaired in DMD, meaning that defective organelles and protein aggregates cannot be readily removed from muscles.
The point here is that the wasting away of muscles in DMD is the source of a plethora of pathology and disability. Since stem cells deal with renewal and change, they are a valid treatment possibility for patients with DMD.
The Role of Satellite Cells
What would the restoration of stem cell function in DMD look like? First, it is important to note that studies have shown that satellite cells directly contribute to the DMD disease phenotype; however, most conventional therapies do not take satellite cells into consideration. For example, two therapeutic strategies that have gained traction over the years—gene delivery by adeno-associated vectors (AAV) and exon skipping with antisense oligonucleotides (AON)—hold great promise but are limited due to poor satellite cell uptake.
“Certain studies have indicated that targeting satellite cells can have therapeutic benefits for DMD,” Filippelli and Chang wrote. For example, a study demonstrates the feasibility of gene editing in satellite cells using CRISPR and adeno-associated virus stereotype-9 to restore dystrophin expression in mdx satellite cells.
Read more about DMD epidemiology
Studies have also shown that the depletion of satellite cells in dystrophic mice during early childhood yields clinical benefits. Scientists concluded that the elimination of dysfunctional satellite cells, combined perhaps with the contribution of dysfunctional mitochondria and deleterious senescent factors, likely led to the improvement of the DMD muscle phenotype.
“Given the dual contribution of dystrophin in muscle tissue and satellite cells, it is imperative to consider stem cell restoration therapy in combination with the current approaches, such as AAV and AON-mediated gene therapy, to provide a combinatorial and synergistic strategy for treating and curing DMD,” Filippelli and Cheng concluded.
References
Kolios G, Moodley Y. Introduction to stem cells and regenerative medicine. Respiration. 2013;85(1):3-10. doi:10.1159/000345615
Filippelli RL, Chang NC. Empowering muscle stem cells for the treatment of Duchenne muscular dystrophy. Cells Tissues Organs. 2021;1-14. doi:10.1159/000514305
Duan D, Goemans N, Takeda S, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nat Rev Dis Primers. 2021;7(1):13. doi:10.1038/s41572-021-00248-3
