Stem cells, chimerism and tolerance: Lessons from mammals and ascidians

Chimerism is the presence of cells derived from more than one individual in a given individual. This phenomenon has been detected in a wide variety of multicellular organisms, including vertebrates. In mammals natural chimerism can develop from bidirectional trafficking of cells between multiple fetuses or between the fetus and its mother during pregnancy. Because stem cells are the only self-renewing cells in a tissue, it is likely that chimerism is sustained by stem cells. Colonial marine ascidians, like Botryllus schlosseri, may serve as an evolutionary model of chimerism. Colonies are initially formed by asexual reproduction of a founder individual, and the progeny clone members are united under a single gelatinous tunic by a network of anastomosed extracorporeal blood vessels. In these organisms, pairs of genetically distinct colonies can establish a natural chimerism upon physical contact by anastomosis of extracorporeal blood vessels between colonies. The ability to create a chimeric entity between colonies is determined by a single, highly polymorphic, fusion/histocompatibility locus (Fu/HC). Colonies that share at least one Fu/HC allele (mainly kin under in situ conditions) fuse vessels upon contact. A pair that does not share any Fu/HC allele does not, but instead has an inflammatory immune response that forms a permanent scar between colonies. Following fusion, cells transmigrate between colonies and, in some cases, replace the germline and/or the somatic tissues of the host. The replacement of host tissues by a donor genotype is pre-determined genetically and follows hierarchies of "winner strains" replacing "loser strains" tissues. In both mammals and ascidians, natural creation of a chimera entity is mainly restricted to kin; long-term chimerism can be established by stem cells; and tolerance of donor tissues can be mediated by chimerism. While several studies and observations across different species, tissues and systems link chimerism to tolerance, its actual role in tolerance induction or maintenance is only understood in experimentally induced mammalian models. Here we review the chimerism phenomenon in mammals and ascidians, discuss the possible role of stem cells as mediators of chimerism and the possible role of cellular chimerism as mediators of tolerance.