Limb Regeneration May Require Less Potent Stem Cells Than Previously Thought
Salamanders have the amazing ability to re-grow a limb after it has been cut off. It is thought that by better understanding this regenerative ability, researchers will be able to apply this knowledge to humans and improve wound healing. Recently it was reported that salamander limb regeneration may occur in a different way than was previously thought; in short, the severed limb may not need pluripotent stem cells to regenerate, as was believed, but only multipotent or unipotent stem cells, stem cells with relatively restricted fates.
In salamanders, when a limb is severed the resultant limb bud undergoes a distinct process to regenerate the lost limb. The epithelial layer quickly spreads across the amputation site, closing the wound within 24 hours (Mescher, 1996). This epithelial layer thickens and becomes what is referred to as the wound epithelium (WE). As the immune system responds to the injury, macrophages and neutrophils arrive to clean up the wound site beneath the WE. The existing injured tissues and cells are broken down as well as the extracellular matrix, which is made up of proteins that surround cells to hold them together and stimulate normal cellular functions. It was thought that at this time in the regenerative process other resident cells below the WE become multipotent mesenchymal stem cells (MSCs) (see Figure). These eventually form a mass of MSCs called a blastema (Mescher, 1996; Brockes and Kumar, 2005). The blastema was thought to contain a homogenous group of pluripotent stem cells that had “dedifferentiated†or “redifferentiated,†meaning they had reverted back from their committed fates to function as very potent stem cells in order to recreate the limb. The WE stimulates the cells in the blastema to proliferate, making new cells and extracellular matrix, though more than is required for simple repair; the WE signals the blastema cells to regenerate the entire lost limb (Mescher, 1996; Kragl et al., 2009).
Limb regeneration in the salamander after limb amputation (time course going from the top down). Shortly after the limb is amputated, the epithelium layer covers the exposed limb bud, forming the wound epithelium (WE). A group of stem cells collects below this layer, forming the blastema (at the tip of the bud). The WE signals the stem cells below it to rebuild the limb, recreating the limb from the point of injury out towards the hand. The final regenerated limb is indistinguishable from the original.
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