Date: 26th February 2020
Extreme muscle loss due to trauma or tumour ablation is extremely difficult to treat in the clinic. Now scientists have integrated neural cells within bioprinted skeletal muscle to accelerate muscle regeneration in vivo.
Extensive muscle defect injuries that impact >20% of original muscle mass often lead to impaired function and have a limited ability to regenerate. Combined with a lack of autologous muscle grafts and donor site morbidity, clinical procedures to help restore this damage are often highly challenging.
A team led by Sang Jin Lee from Wake Forest School of Medicine, US, had previously demonstrated that an Integrated Tissue and Organ Printing System (ITOP) could bioprint an implantable and biomimetic human skeletal muscle construct in rodents. However, the team wanted to improve the technique further as the constructs did not fully support the restoration of defected muscles likely due to a delay in integration of the host nerve system.
In order to address this they developed human skeletal muscle constructs with neural cells integrated by bioprinting human muscle progenitor cells (hMPCs) and human neural stem cells (hNSCs) together and then assessing their function in a pre-clinical rodent model.
- The effects of neural cells on skeletal muscle differentiation (correct myotube formation) was determined by 2D cell culture experiments enabling optimisation of the ratio of hMPCs to hNSCs.
- Subsequent bioprinting of the 3D layered human skeletal muscle constructs showed an increase in cell survival, muscle differentiation and maturation, and innervation potential when compared to those created using just hMPCs in vitro.
- The bioprinted skeletal muscle constructs were then implanted into rodent extensive-injury models.
- Both hMPCs muscle constructs and hMPCs+hNSCs constructs were able to restore muscle weight at 8-weeks post implantation. However, a much more rapid recovery was seen in the hMPC +h NSC group at 4 weeks of implantation.
- Muscle function was also restored, with 71.42% restoration of muscle force in the hMPCs group, and 100% restoration in the hMPCs+hNSCs group when compared with the control animals (at 8 weeks post implantation).
- The constructs were also able to facilitate rapid nerve distribution, mature organised muscle tissue and vascularisation.
Conclusions and future developments
This study presents a promising development for a new therapeutic option to reconstructive surgery. The muscle constructs were able to facilitate accelerated innervation and restore normal muscle anatomy and function in rat muscle defect models.
The hNSCs within the bioprinted tissue were able to differentiate into neurons and glial cells, and these neural cell components seemed to readily induce neuromuscular junction formation, which is known to be critical for skeletal muscle survival, development, maturation, and contraction.
Further, In-depth validation and refinement of the molecular, biological, and physiological aspects of the innervation and skeletal muscle regeneration process in the bioprinted constructs is reportedly underway. Future studies will also delve deeper into the contractile function of the bioengineered constructs.
From a clinical perspective the safety and efficacy of using autologous hMPCs for cell-based therapies has already been demonstrated in several clinical trials. However, it remains to be determined whether the approach of harvesting, isolating, and expanding hNSCs will be clinically practical. With other options available for example it may be possible to identify and isolate potential neurotrophic factors released from the neural cell that are responsible for the effect, hopefully this won’t be a limiting factor for progressing this treatment.
We are seeing rapid advancements in bioprinting, including the development of bioinks and hydrogels such that organs or tissues that were once deemed too tricky to be supported by the technique such as the ‘flexible’ beating heart are becoming are an increasing reality. We have even seen organs bioprinted in space in the bid to circumvent the global organ donor shortage. This new development should be yet another step forward in the drive towards organ and tissue replacements.
For more information please see the press release from Wake Forest Baptist Medical Center
Kim, J. H., I. Kim, Y.-J. Seol, I. K. Ko, J. J. Yoo, A. Atala and S. J. Lee (2020). “Neural cell integration into 3D bioprinted skeletal muscle constructs accelerates restoration of muscle function.” Nature Communications 11(1): 1025.
https://doi.org/10.1038/s41467-020-14930-9
