Concise Review: Non-cell Autonomous Reprogramming: A Nucleic Acid-Free Approach to Induction of Pluripotency

Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198-5840, USA.
Stem Cells (Impact Factor: 6.52). 07/2011; 29(7):1013-20. DOI: 10.1002/stem.655
Source: PubMed


The reprogramming of somatic cells to a pluripotent state by the expression of a defined set of exogenous transcription factors represents a significant breakthrough for the use of stem cells in regenerative medicine. It has the potential to make autologous stem cell therapy practical and promote better understanding of the disease processes by generating patient specific stem cells. Several strategies have been used to generate induced pluripotent stem cells (iPSCs) that include nucleic acid and non-nucleic acid-based approaches, with and without epigenetic modifications. The purpose of these different approaches for generating iPSCs, besides understanding the underlying mechanism, is to develop a facile method for reprogramming without genetic alteration, suitable for clinical use. Here, we discuss different strategies for generating iPSCs, with an emphasis on a recent non-cell autonomous approach to reprogram somatic progenitors that regenerate cornea to a pluripotent state through the recruitment of endogenous transcription factors.

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Available from: Mahendra Surendra Rao
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    • "The mechanism of ES cell-mediated induction of pluripotency in limbal progenitors remains to be elucidated. It is likely to include soluble ligands activating intercellular signaling pathways influencing the network of pluripotency genes [35]. In addition, the involvement of ES cell cycle (ESCC)-specific miRNAs, which are observed to regulate ES cell self-renewal [40], reprogram human fibroblasts [6], and can be potentially imported via exosomes in the ESCM, is worth consideration. "
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    ABSTRACT: Reprogramming somatic cells to a pluripotent state by nucleic acid based (NAB) approaches, involving the ectopic expression of transcription factors, has emerged as a standard method. We recently demonstrated that limbal progenitors that regenerate cornea are reprogrammable to pluripotency by a non-NAB approach through simple manipulation of microenvironment thus extending the possible therapeutic use of these readily accessible cells beyond the proven treatment of corneal diseases and injury. Therefore, to determine the validity and robustness of non-cell autonomous reprogramming of limbal progenitors for a wider clinical use, here, we have compared their reprogramming by non-NAB and NAB approaches. We observed that both approaches led to (1) the emergence of colonies displaying pluripotency markers, accompanied by a temporal reciprocal changes in limbal-specific and pluripotency gene expression, and (2) epigenetic alterations of Oct4 and Nanog, associated with the de-novo activation of their expression. While the efficiency of reprogramming and passaging of re-programmed cells were significantly better with the NAB approach, the non-NAB approach, in contrast, led to a regulated reprogramming of gene expression, and a significant decrease in the expression of Hormad1, a gene associated with immunogenic responses. The reprogramming efficiency by non-NAB approach was influenced by exosomes present in conditioned medium. Cells reprogrammed by both approaches were capable of differentiating along the three germ lineages and generating chimeras. The analysis suggests that both approaches are effective in reprogramming limbal progenitors but the non-NAB approach may be more suitable for potential clinical applications by averting the risk of insertional mutagenesis and immune responses associated with the NAB approach.
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