Abstract
Pre-clinical and clinical studies are now beginning to demonstrate the high potential of cell therapies in enhancing muscle regeneration. We previously demonstrated functional benefit after the transplantation of autologous bone marrow mesenchymal stromal cells (MSC-TX) into a severe muscle crush trauma model. Despite our increasing understanding of the molecular and cellular mechanisms underlying MSC’s regenerative function, little is known about the local molecular alterations and their spatial distribution within the tissue after MSC-TX. Here, we used MALDI imaging mass spectrometry (MALDI-IMS) in combination with multivariate statistical strategies to uncover previously unknown peptide alterations within severely injured skeletal muscles. Our analysis revealed that very early molecular alterations in response to MSC-TX occur largely in the region adjacent to the trauma and only to a small extent in the actual trauma region. Using “bottom up” mass spectrometry, we subsequently identified the proteins corresponding to the differentially expressed peptide intensity distributions in the specific muscle regions and used immunohistochemistry to validate our results. These findings extend our current understanding about the early molecular processes of muscle healing and highlights the critical role of trauma adjacent tissue during the early therapeutic response upon treatment with MSC.
Highlights
Skeletal muscles have a significant regenerative potential
We found that ion intensity of m/z values of Hspa[8] significantly increased in the tam as well as in tm region of Mesenchymal stromal cells (MSCs)-TX treated muscles compared to the control (AUC 1.2 and
An ever-increasing number of reports suggest that the transplantation of MSCs from different sources improves the regeneration in a wide range of disease related to muscle tissue, including muscular dystrophy, cardiomyopathy, and severely injured skeletal muscles[7,21,22,23]
Summary
Skeletal muscles have a significant regenerative potential. these endogenous processes are often insufficient to recover from severe injuries, leading to fatty degeneration and scar formation, which compromise muscle function and its structural integrity[1]. Mesenchymal stromal cells (MSCs) are promising cell source for such applications due to their immunomodulatory, paracrine, and differentiation potential[4] Their regenerative capability has already been validated in several animal models of muscular dystrophy, myocardial infarction, and skeletal muscle trauma. The characterization of the muscle proteome after injury and how it is altered after cell therapy could elucidate mechanisms by which MScs induce muscle regeneration and may enable the discovery of new therapeutic targets for directed interventions This is challenging because such an endeavor requires the spatial assessment of local molecular alterations within the injured muscle. G. 2D gel electrophoresis or liquid chromatography (LC) based mass spectrometry[11,12] These techniques do not enable a direct correlation between differentially expressed protein profiles and the tissue histology. Thereby, the primary traumatized muscle region can be distinguished from trauma adjacent tissue via the lower intensity distribution of the muscle proteins carbonic anhydrase III (Ca3) and skeletal muscle alpha actin (Acts)
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