Abstract
Background and MethodsIn this study, we utilized a combination of low oxygen tension and a novel anti-oxidant, 4-(3,4-dihydroxy-phenyl)-derivative (DHP-d) to directly induce adipose tissue stromal cells (ATSC) to de-differentiate into more primitive stem cells. De-differentiated ATSCs was overexpress stemness genes, Rex-1, Oct-4, Sox-2, and Nanog. Additionally, demethylation of the regulatory regions of Rex-1, stemnesses, and HIF1α and scavenging of reactive oxygen species were finally resulted in an improved stem cell behavior of de-differentiate ATSC (de-ATSC). Proliferation activity of ATSCs after dedifferentiation was induced by REX1, Oct4, and JAK/STAT3 directly or indirectly. De-ATSCs showed increased migration activity that mediated by P38/JUNK and ERK phosphorylation. Moreover, regenerative efficacy of de-ATSC engrafted spinal cord-injured rats and chemical-induced diabetes animals were significantly restored their functions.Conclusions/SignificanceOur stem cell remodeling system may provide a good model which would provide insight into the molecular mechanisms underlying ATSC proliferation and transdifferentiation. Also, these multipotent stem cells can be harvested may provide us with a valuable reservoir of primitive and autologous stem cells for use in a broad spectrum of regenerative cell-based disease therapy.
Highlights
The classic definition of cell plasticity from stem cell biology specifies the ability of stem cells to differentiate into a variety of cell lineages, the term is currently applied to the ability of a given cell type to reciprocally dedifferentiate, redifferentiate, and/or trans-differentiate in response to specific stimuli [1,2]
Our results show that adipose tissue stromal cells (ATSC) can undergo an increase in developmental potential following reprogramming via the overexpression of the embryonic transcription factor, Rex1, Oct4, and Oct4-dependent Nanog and Sox2
Our results indicated that hypoxia and DHP-d can activate MEK and ERK1/2 within a few days of de-differentiation induction
Summary
The classic definition of cell plasticity from stem cell biology specifies the ability of stem cells to differentiate into a variety of cell lineages, the term is currently applied to the ability of a given cell type to reciprocally dedifferentiate, redifferentiate, and/or trans-differentiate in response to specific stimuli [1,2]. This process characterizes the transition of differentiated somatic cells to pluripotent stem cells, and is accompanied by global chromatin reorganization, which is itself associated with the reprogramming of gene expression. Dedifferentiation signifies the withdrawal of cells from a given differentiated state into a stem cell-like state, which confers pluripotency, a process that precedes re-entry into the cell cycle [3]. We utilized a combination of low oxygen tension and a novel anti-oxidant, 4-(3,4dihydroxy-phenyl)-derivative (DHP-d) to directly induce adipose tissue stromal cells (ATSC) to de-differentiate into more primitive stem cells. De-differentiated ATSCs was overexpress stemness genes, Rex-1, Oct-4, Sox-2, and Nanog. Proliferation activity of ATSCs after dedifferentiation was induced by REX1, Oct, and JAK/STAT3 directly or indirectly. Regenerative efficacy of de-ATSC engrafted spinal cord-injured rats and chemical-induced diabetes animals were significantly restored their functions
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