Combining Cell Reprogramming and Scaffold Materials for Muscle Regrowth

A well established field of research is focused on the development of implantable scaffold materials to encourage regeneration of lost tissue, such as in the case of severe muscle injuries. A wide variety of scaffold approaches incorporate signaling molecules and increasingly sophisticated small-scale structure, all intended to mimic aspects of the natural extracellular matrix, as well as other features. Use of a natural extracellular matrix is also an option, via decellularization of donor tissue. A great deal of innovation is taking place. As an example, researchers here combine a scaffolding approach with cell reprogramming to demonstrate muscle regrowth in an animal model.

In serious injuries such as those sustained in car accidents or tumor resection which results in a volumetric muscle loss (VML), the muscle's ability to recover is greatly diminished. A promising strategy to improve the functional capacity of the damaged muscle is to induce de novo regeneration of skeletal muscle via the integration of transplanted cells. Diverse types of cells, including satellite cells (muscle stem cells), myoblasts, and mesenchymal stem cells, have been used to treat muscle loss.

An important issue is controlling the three-dimensional microenvironment at the injury site to ensure that the transplanted cells properly differentiate into muscle tissues with desirable structures. A variety of natural and synthetic biomaterials have been used to enhance the survival and maturation of transplanted cells while recruiting host cells for muscle regeneration. However, there are unsolved, long-lasting dilemmas in tissue scaffold development. Natural scaffolds exhibit high cell recognition and cell binding affinity, but often fail to provide mechanical robustness in large lesions or load-bearing tissues that require long-term mechanical support. In contrast, synthetic scaffolds provide a precisely engineered alternative with tunable mechanical and physical properties, as well as tailored structures and biochemical compositions, but are often hampered by lack of cell recruitment and poor integration with host tissue.

To overcome these challenges, a research team has devised a novel protocol for artificial muscle regeneration. The team achieved effective treatment of VML in a mouse model by employing direct cell reprogramming technology in combination with a natural-synthetic hybrid scaffold. Direct cell reprogramming, also called direct conversion, is an efficient strategy that provides effective cell therapy because it allows the rapid generation of patient-specific target cells using autologous cells from the tissue biopsy. Fibroblasts are the cells that are commonly found within the connective tissues, and they are extensively involved in wound healing. As the fibroblasts are not terminally differentiated cells, it is possible to turn them into induced myogenic progenitor cells (iMPCs) using several different transcription factors. Herein, this strategy was applied to provide iMPC for muscle tissue engineering.

In order to provide structural support for the proliferating muscle cells, polycaprolactone (PCL), was chosen as a material for the fabrication of a porous scaffold due to its high biocompatibility. However, the synthetic PCL fiber scaffolds alone do not provide optimal biochemical and local mechanical cues that mimic muscle-specific microenvironment. Hence the construction of a hybrid scaffold was completed through the incorporation of decellularized muscle extracellular matrix (MEM) hydrogel into the PCL structure.

The resultant bioengineered muscle fiber constructs showed mechanical stiffness similar to that of muscle tissues and exhibited enhanced muscle differentiation and elongated muscle alignment in vitro. Furthermore, implantation of bioengineered muscle constructs in the VML mouse model not only promoted muscle regeneration with increased innervation and angiogenesis but also facilitated the functional recovery of damaged muscles.



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