#apaperaday: Transplantation of Differentiated Tonsil-Derived Mesenchymal Stem Cells Ameliorates Murine Duchenne Muscular Dystrophy via Autophagy Activation

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Transplantation of Differentiated Tonsil-Derived Mesenchymal Stem Cells Ameliorates Murine Duchenne Muscular Dystrophy via Autophagy Activation

Today’s pick is from Tissue Engineering Regenerative Medicine by Park et al on transplantation of tonsil derived stem cells in the mdx mouse model. I am a bit confused by it. Doi 10.1007/s13770-022-00489-7

Muscle is an abundant tissue and it has functions for moving but also for metabolism (keeping us warm for instance). After damage muscle can regenerate. For muscle wasting diseases like Duchenne, stem cell therapies have been proposed before even the mutated gene was identified.

Authors here propose mesenchymal stem cell as a good source for stem cells. When these stem cells are isolated from tonsils they can differentiate into different cell types, including muscle when provided with the proper growth factors.

Authors first show that the tonsil derived stem cells (isolated from tonsils that were removed from humans) can differentiate into myotubes. Then they transplanted them into mouse gastrocnemius with local injection.

It is not clear whether they injected the differentiated cells or cells cultured for 4 weeks…They analyze dystrophin levels in sham treated mdx, treated mdx and wild type controls.They claim a slightly higher expression of dystrophin in treated mdx (TP)

Authors also see a reduction in damage after treatment, though nowhere near wild type levels. Finally, they assess autophagy markers – here is where I get confused. They see more autophagy after the transplantation they claim, but I am not convinced.

LC3 indeed increases in TP, but p62 is much higher in untreated than wild type and goes down in treated mice. So I do not understand how authors conclude that the transplantation ameliorates histology via autophagy?

Authors discuss that they still have to study how long dystrophin restoration persists after treatment (now it was analyzed until 12 weeks). They do discuss that there was some contradictory correlation for the autophagy – further studies are needed to elucidate.

They conclude that the results show that this type of stem cell transplantation is promising for muscle diseases. I won’t agree – it is way too early for this yet. All they showed is some local dystrophin restoration after local injection of an mdx mouse.

You cannot do this in humans – and you cannot even inject each muscle in an mdx mouse. Also the sheer number of stem cells you would need if it was possible to do local injections (millions) in humans probably would make this approach unfeasible.

If we want to make stem cell treatment work for treating muscle diseases, we have to take a step by step approach and as a field we can celebrate each little success. HOWEVER, we then should also paint a realistic picture of what is still to be done – authors failed to do this…