Thymosin β4-Enhancing Therapeutic Efficacy of Human Adipose-Derived Stem Cells in Mouse Ischemic Hindlimb Model.
Jong-Ho KimI-Rang LimChi-Yeon ParkHyung Joon JooJi-Min NohSeung-Cheol ChoiSoon Jun HongDo-Sun LimPublished in: International journal of molecular sciences (2020)
Thymosin β4 (Tβ4) is a G-actin sequestering protein that contributes to diverse cellular activities, such as migration and angiogenesis. In this study, the beneficial effects of combined cell therapy with Tβ4 and human adipose-derived stem cells (hASCs) in a mouse ischemic hindlimb model were investigated. We observed that exogenous treatment with Tβ4 enhanced endogenous TMSB4X mRNA expression and promoted morphological changes (increased cell length) in hASCs. Interestingly, Tβ4 induced the active state of hASCs by up-regulating intracellular signaling pathways including the PI3K/AKT/mTOR and MAPK/ERK pathways. Treatment with Tβ4 significantly increased cell migration and sprouting from microbeads. Moreover, additional treatment with Tβ4 promoted the endothelial differentiation potential of hASCs by up-regulating various angiogenic genes. To evaluate the in vivo effects of the Tβ4-hASCs combination on vessel recruitment, dorsal window chambers were transplanted, and the co-treated mice were found to have a significantly increased number of microvessel branches. Transplantation of hASCs in combination with Tβ4 was found to improve blood flow and attenuate limb or foot loss post-ischemia compared to transplantation with hASCs alone. Taken together, the therapeutic application of hASCs combined with Tβ4 could be effective in enhancing endothelial differentiation and vascularization for treating hindlimb ischemia.
Keyphrases
- cell therapy
- endothelial cells
- signaling pathway
- cell migration
- blood flow
- stem cells
- high glucose
- gene expression
- spinal cord
- mesenchymal stem cells
- metabolic syndrome
- type diabetes
- cell proliferation
- insulin resistance
- risk assessment
- ischemia reperfusion injury
- small molecule
- induced pluripotent stem cells
- transcription factor
- blood brain barrier
- diabetic rats
- single cell
- dna methylation
- pluripotent stem cells
- binding protein
- reactive oxygen species
- protein protein
- single molecule
- high speed