Transplantation of Adipose Stromal Cell Sheet Producing Hepatocyte Growth Factor Induces Pleiotropic Effect in Ischemic Skeletal Muscle

Abstract

Cell therapy remains a promising approach for the treatment of cardiovascular diseases. In this regard, the contemporary trend is the development of methods to overcome low cell viability and enhance their regenerative potential. In the present study, we evaluated the therapeutic potential of gene-modified adipose-derived stromal cells (ADSC) that overexpress hepatocyte growth factor (HGF) in a mice hind limb ischemia model. Angiogenic and neuroprotective effects were assessed following ADSC transplantation in suspension or in the form of cell sheet. We found superior blood flow restoration, tissue vascularization and innervation, and fibrosis reduction after transplantation of HGF-producing ADSC sheet compared to other groups. We suggest that the observed effects are determined by pleiotropic effects of HGF, along with the multifactorial paracrine action of ADSC which remain viable and functionally active within the engineered cell construct. Thus, we demonstrated the high therapeutic potential of the utilized approach for skeletal muscle recovery after ischemic damage associated with complex tissue degenerative effects.

Effects of ASC Application on Endplate Regeneration Upon Glycerol-Induced Muscle Damage

“…While local injection might come with a higher potential for targeted cell integration, it is difficult to achieve for diseases where different organs or large parts of the body are affected, as it is true for most neuromuscular disorders (Gois et al, 2019). On the other hand, while systemic application might have a drawback in the entrapment of most injected cells in organs such as lungs and liver (Gois et al, 2019) recent studies suggest that a principal function of stem cell therapies relies in their modulatory activities on cellular signaling rather than direct cell engraftment (Gorecka et al, 2018;Boldyreva et al, 2019;Mitchell et al, 2019;Torres-Torrillas et al, 2019). Although in different animal models and clinical applications beneficial effects of stem cell grafts on recovery of muscle tissue were reported (Forcales, 2015;Torres-Torrillas et al, 2019), little emphasis has been put on their impact at the level of the neuromuscular junction (NMJ).…”

Cell Sheet Comprised of Mesenchymal Stromal Cells Overexpressing Stem Cell Factor Promotes Epicardium Activation and Heart Function Improvement in a Rat Model of Myocardium Infarction

“…Within a multilayered construct, the cells retain their intercellular junctions, interaction with organized extracellular matrix and thus reside in close to native microenvironment. Our previous observations supported by other studies demonstrate the increased survival and therapeutic potential of CSs comprised of MSC in hind limb ischemia and peripheral nerve degeneration models [23,[37][38][39]. To augment the therapeutic potential of MSCs and to confer more regenerative capacity we modified them to produce high levels of SCF.…”

“…Rat adipose-derived MSCs were transduced with the recombinant adeno-associated virus (AAV) encoding the rat SCF gene. The AAV-DJ serotype used was previously shown to provide up to 80–90% efficacy of rodent MSCs transduction [ 23 ]. The level of SCF secretion by generated SCF-MSCs, evaluated by immunosorbent assay, peaked at day 9 post viral transduction reaching 60.97 ± 11.48 pg/mL (adjusted per 1 × 10 3 cells).…”

“…In another study, we demonstrated neuroprotective potential of conditioned medium from adipose derived MSCs, overexpressing hepatocyte growth factor (HGF), that increased neurite outgrowth and glial cell migration in the dorsal root ganglion explant model. Upon transplantation, these cells stimulated nerve growth in ischemic skeletal muscle [ 23 ].…”

Cell Sheets from Adipose Tissue MSC Induce Healing of Pressure Ulcer and Prevent Fibrosis via Trigger Effects on Granulation Tissue Growth and Vascularization

“…Finally, the ability of MSC to form tissue-like constructs composing of viable cells and their native ECM resulted in the development of cell sheets (CS)-minimal tissue-engineered constructs that found application for many conditions. Our previous experience with MSC-based CS showed their efficacy for stimulation of angiogenesis, nerve repair and cardiac regeneration and proved their superiority over routinely used local injection [10][11][12][13][14]. The latter has been shown to induce MSC apoptosis and its rapid clearance from blood flow or tissue (muscle, myocardium, etc.).…”