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.
Highlights
Decades of experimental and clinical research in the field of peripheral vascular disease have still not led to the full-scale translation of therapeutic angiogenesis techniques into clinical practice
The present study focuses on the potential to recover vascular and neural trophic in ischemic skeletal muscle after delivery of a multilayered cell sheet comprised of hepatocyte growth factor (HGF)-expressing mesenchymal stromal cells (MSC) sheets in a mouse model of limb ischemia
Mouse adipose-derived stromal cells (ADSC) were transduced with chimeric adeno-associated viral vector serotype (AAV-DJ) encoding mHGF or green fluorescent protein (GFP)
Summary
Decades of experimental and clinical research in the field of peripheral vascular disease have still not led to the full-scale translation of therapeutic angiogenesis techniques into clinical practice. Current pharmacological management of ischemic disorders mostly addresses metabolic risk factors, while surgical revascularization is applied at an advanced stage of disease to prevent critical tissue damage or organ loss, though this is inapplicable for a large cohort of patients due to elder age, obesity and other comorbidities. The use of recombinant proteins and gene therapy methods failed to reach primary endpoints in clinical trials of therapeutic angiogenesis [1,2]. This is believed to have happened due to a short residence time for recombinant factors, insufficient tissue transduction by genetically engineered constructs and, above all, the limited therapeutic potential of these stimuli introduced as a monotherapy
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