Can RNA interference be used to expand the plasticity of autologous adult stem cells?

Abstract

Adult stem cells have tremendous potential in regenerative medicine [1]. Because immunorejection is undoubtedly the most formidable challenge in stem cell-transplantation therapy [2], the autologous transplantation of adult stem cells is preferred over the allogenic transplantation of either adult or embryonic stem (ES) cells. Although therapeutic cloning for the production of isogenic ES cells has recently been achieved in the human model [3], many outstanding technical difficulties must be overcome [4] before this can materialize into a viable mode of clinical therapy. Recent studies have demonstrated the extensive plasticity of adult stem cells, but this remains a highly controversial issue [5, 6, 7]. In many cases the differentiation capacity of autologous adult stem cells appears to be strongly biased towards lineages that are characteristic of the tissue or organ from which they originate. With the possible exception of bone-marrow derived mesenchymal stem cells [8] the observed transdifferentiation of all other types of putative adult stem cells seems to be relatively rare and sporadic [6]. Even with bone-marrow derived mesenchymal stem cells there appears to be a strong bias in differentiation towards a limited number of mesodermal lineages, such as the osteogenic, chondrogenic, myogenic, and adipogenic lineages [9, 10]. The limited multipotency of adult stem cells could severely restrict their application in autologous celltransplantation therapy. Obviously it would not be possible to harvest autologous adult stem cells from diseased or damaged tissues and organs that are in dire need of therapeutic intervention. Instead it would be much more practical to extract autologous adult stem cells from other healthy tissues of the same patient and to manipulate these cells to regenerate the damaged/diseased tissue or organ. Hence it is imperative to develop strategies to expand the plasticity of autologous adult stem cells, thereby enabling them to differentiate into a greater variety of other lineages. Only then can the full potential of autologous adult stem cells in regenerative medicine be realized. A promising strategy for expanding the plasticity of autologous adult stem cells is through downregulation of gene expression by RNA interference [11, 12]. To summarize briefly, the RNA interference pathway involves processing of long double-stranded RNA (dsRNA) into 2125-bp small interfering RNAs (siRNA) by an RNase III-like enzyme called Dicer [13, 14]. The siRNA is then incorporated within a multisubunit RNAinduced silencing complex (RISC), which specifically targets homologous cellular mRNA transcripts for degBoon Chin Heng received his Ph.D. degree in biochemistry from the University of Manchester, UK. He is currently a Singapore Millennium Foundation Post-Doctoral Fellow and is based at the Faculty of Dentistry of the National University of Singapore. His research interests are focused on adult and embryonic stem cell differentiation. Tong Cao received his Ph.D. from Showa University Graduate School in Tokyo, Japan. He is currently Assistant Professor in the Faculty of Dentistry of the National University of Singapore, and Principal Investigator of the Stem Cell Research Program. His research interests include adult and embryonic stem cell differentiation.