Restitutio ad integrum: a dream or a real possibility?

The subject of organ regeneration has attracted substantial investigative attention and has been extensively reviewed. Therefore, I shall focus on several only recently emerged issues and on those aspects of stem cell-mediated regeneration which, although are important in my opinion, have nevertheless evaded the radar of scientific pursuit. Specifically, I shall describe the recent work on the prominence of local lineage-restricted stem cells, as opposed to the bone marrow-derived or circulating ones, in regeneration. This will be followed by an attempt to re-interpret a bulk of published data on the beneficial effects of cell therapy with the focus on the secretome of stem cells. Multiple factors that conspire to cause insufficient or failed regeneration in adult mammals will be screened with emphasis placed on the mechanical forces, senescence and exhaustion, each leading to phenotypical switch and/or stem cell incompetence. Finally, I shall enumerate several potential pathways to induce or restore stem cell competence. Although a significant amount of work has been performed in the non-renal field, I would hope that some of the mechanisms and concepts discussed herein will eventually trickle into kidney regeneration.