Mechanical Stretching Promotes Skin Tissue Regeneration via Enhancing Mesenchymal Stem Cell Homing and Transdifferentiation

Abstract

Skin tissue expansion is a clinical procedure for skin regeneration to reconstruct cutaneous defects that can be accompanied by severe complications. The transplantation of mesenchymal stem cells (MSCs) has been proven effective in promoting skin expansion and helping to ameliorate complications; however, systematic understanding of its mechanism remains unclear. MSCs from luciferase-Tg Lewis rats were intravenously transplanted into a rat tissue expansion model to identify homing and transdifferentiation. To clarify underlying mechanisms, a systematic approach was used to identify the differentially expressed genes between mechanically stretched human MSCs and controls. The biological significance of these changes was analyzed through bioinformatic methods. We further investigated genes and pathways of interest to disclose their potential role in mechanical stretching-induced skin regeneration. Cross sections of skin samples from the expanded group showed significantly more luciferase + and stromal cell-derived factor 1a (SDF-1a) + cells than the control group, indicating MSC transdifferentiation into epidermal basal cells and endothelial cells after SDF-1a-mediated homing. Microarray analysis suggested upregulation of genes related to hypoxia, vascularization, and cell proliferation in the stretched human MSCs. Further investigation showed that the homing of MSCs was blocked by short interfering RNA targeted against matrix metalloproteinase 2, and that mechanical stretching-induced vascular endothelial growth factor A upregulation was related to the Janus kinase/signal transducer and activator of transcription (Jak-STAT) and Wnt signaling pathways. This study determines that mechanical stretching might promote skin regeneration by upregulating MSC expression of genes related to hypoxia, vascularization, and cell proliferation; enhancing transplanted MSC homing to the expanded skin; and transdifferentiation into epidermal basal cells and endothelial cells. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:960-969 SIGNIFICANCESkin tissue expansion is a clinical procedure for skin regeneration to cover cutaneous defects that can be accompanied by severe complications. The transplantation of mesenchymal stem cells (MSCs) has been proven effective in promoting skin expansion and ameliorating complications. This study, which sought to provide a systematic understanding of the mechanism, determined that mechanical stretching could upregulate MSC expression of genes related to hypoxia, vascularization, and cell proliferation; enhance transplanted MSC homing to the expanded skin tissue; and promote their transdifferentiation into epidermal basal cells and endothelial cells.

A biomaterial approach to cell reprogramming and differentiation

“…By inhibiting each of these processes, this network subsequently could not be seen in vitro , proving that this signaling network is the key component to cell differentiation via environmental change [104]. Other studies suggest that mechanical stretching can even regenerate skin tissue [105]. Stretching could upregulate gene expression related to cell proliferation, vascularization, etc.…”

The question of the influence of the dosed tissue stretching on the concentration of the hypoxia-inducible factor (HIF-1α) in the stretched flap

“…The concentration of HIF-1α in the skin before the start of the dermotension was (Me [Q1; Q3]) 110 [98,1; 114,8] ng/ml. A statistically significant increase in the concentration of 2; 221,7] ng/ml (p=0.008) recorded in the group of animals who underwent tissue stretching within 30 minutes, research also showed that the concentration of 4; 463,3] ng/ml (p=0.007) after 24 hours from the start of the dosed strains. Conclusion.…”

“…Концентрация HIF-1α в коже до начала дермотензии составляла (Ме [Q1; Q3]) 110 [98,1; 114,8] нг/мл. В группе животных, которым выполняли тканевое растяжение в течение 30 минут зафиксировано статистически значимое увеличение концентрации 2; 221,7] нг/мл (р=0,008), через 24 часа от начала дозированного растяжения, выявлено,4; 463,3] нг/мл (р=0,007). Вывод.…”

“…Вместе с ростом частоты применения способа все глубже исследовались сопутствующие ему феномены, и, в первую очередь, -тканевая гипоксия, возникающая в процессе растяжения в результате уменьшения диаметра сосудов [5]. Гистологическими исследованиями установлено, что при дозированной тракции в сосудах дермы и подкожной клетчатки не выявляется значимых структурных повреждений, наоборот, в растягиваемой ткани выявляется быстрая пролиферация кровеносных сосудов [6,7]. В условиях гипоксии активность пролиферативных процессов и ангиогенез, то есть развитие новых сосудов из уже имеющихся, регулируются открытым в 1992 году американским ученым G.L.…”

Repair Effect of Mesenchymal Stem Cells on Fracture Model Animals

“…Mesenchymal stem cells (MSCs) are widely distributed in the tissues of bone marrow, fat, periosteum, muscle, synovium, tendon, umbilical cord blood, pulp, peripheral blood vessels. The isolated mesenchymal stem cells can be separated from these tissues with multiple differentiation potential, with high self-renewal ability and proliferation ability [5]. It can differentiate into bone, cartilage, fat, muscle, tendon, vascular endothelial cells and nerve cells under different induction and differentiation conditions.…”