Stem cells are units of natural selection for tissue formation, for germline development, and in cancer development

It is obvious that natural selection operates at the level of individuals and collections of individuals. Nearly two decades ago we showed that in multi-individual colonies of protochordate colonial tunicates sharing a blood circulation, there exists an exchange of somatic stem cells and germline stem cells, resulting in somatic chimeras and stem cell competitions for gonadal niches. Stem cells are unlike other cells in the body in that they alone self-renew, so that they form clones that are perpetuated for the life of the organism. Stem cell competitions have allowed the emergence of competitive somatic and germline stem cell clones. Highly successful germline stem cells usually outcompete less successful competitors both in the gonads of the genotype partner from which they arise and in the gonads of the natural parabiotic partners. Therefore, natural selection also operates at the level of germline stem cell clones. In the colonial tunicate Botryllus schlosseri the formation of natural parabionts is prevented by a single-locus highly polymorphic histocompatibility gene called Botryllus histocompatibility factor. This limits germline stem cell predation to kin, as the locus has hundreds of alleles. We show that in mice germline stem cells compete for gonad niches, and in mice and humans, blood-forming stem cells also compete for bone marrow niches. We show that the clonal progression from blood-forming stem cells to acute leukemias by successive genetic and epigenetic events in blood stem cells also involves competition and selection between clones and propose that this is a general theme in cancer.

[1]  I. Weissman,et al.  Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission , 2014, Proceedings of the National Academy of Sciences.

[2]  Debashis Sahoo,et al.  Identification of a Colonial Chordate Histocompatibility Gene , 2013, Science.

[3]  Aaron M. Newman,et al.  The genome sequence of the colonial chordate, Botryllus schlosseri , 2013, eLife.

[4]  I. Weissman,et al.  Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes , 2013, Proceedings of the National Academy of Sciences.

[5]  I. Weissman,et al.  Clonal Evolution of Preleukemic Hematopoietic Stem Cells Precedes Human Acute Myeloid Leukemia , 2012, Science Translational Medicine.

[6]  Jens-Peter Volkmer,et al.  The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors , 2012, Proceedings of the National Academy of Sciences.

[7]  I. Weissman,et al.  Programmed cell removal: a new obstacle in the road to developing cancer , 2011, Nature Reviews Cancer.

[8]  I. Weissman,et al.  Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion , 2010, Proceedings of the National Academy of Sciences.

[9]  I. Weissman,et al.  CD47 Is Upregulated on Circulating Hematopoietic Stem Cells and Leukemia Cells to Avoid Phagocytosis , 2009, Cell.

[10]  Ash A. Alizadeh,et al.  CD47 Is an Adverse Prognostic Factor and Therapeutic Antibody Target on Human Acute Myeloid Leukemia Stem Cells , 2009, Cell.

[11]  L. Hood,et al.  Dysregulated gene expression networks in human acute myelogenous leukemia stem cells , 2009, Proceedings of the National Academy of Sciences.

[12]  I. Weissman,et al.  Two-step oligoclonal development of male germ cells , 2009, Proceedings of the National Academy of Sciences.

[13]  I. Weissman,et al.  Stems Cells and the Pathways to Aging and Cancer , 2008, Cell.

[14]  Mark S. Anderson,et al.  Apoptosis in Spermatogenesis Expression of Aire and the Early Wave of , 2022 .

[15]  G. Hannon,et al.  MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline. , 2007, Developmental cell.

[16]  I. Weissman,et al.  Clonal analysis of mouse development reveals a polyclonal origin for yolk sac blood islands. , 2006, Developmental cell.

[17]  I. Weissman,et al.  Stem cell research: paths to cancer therapies and regenerative medicine. , 2005, JAMA.

[18]  I. Weissman,et al.  Telomerase maintained in self-renewing tissues during serial regeneration of the urochordate Botryllus schlosseri. , 2004, Developmental biology.

[19]  Laurie E Ailles,et al.  Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. , 2004, The New England journal of medicine.

[20]  I. Weissman,et al.  Hematopoietic stem cells and other hematopoietic cells show broad resistance to chemotherapeutic agents in vivo when overexpressing bcl-2. , 2003, Experimental hematology.

[21]  I. Weissman,et al.  AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[22]  I. Weissman,et al.  Stem Cells Units of Development, Units of Regeneration, and Units in Evolution , 2000, Cell.

[23]  I. Weissman,et al.  Heritable germ and somatic cell lineage competitions in chimeric colonial protochordates. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[24]  I. Weissman,et al.  Two distinct pathways of positive selection for thymocytes. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Irene Garcia,et al.  An early and massive wave of germinal cell apoptosis is required for the development of functional spermatogenesis , 1997, The EMBO journal.

[26]  I. Weissman,et al.  Somatic and germ cell parasitism in a colonial ascidian: possible role for a highly polymorphic allorecognition system. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[27]  I. Weissman,et al.  bcl-2 inhibits apoptosis of neutrophils but not their engulfment by macrophages , 1994, The Journal of experimental medicine.

[28]  I. Weissman,et al.  A long‐term study on fused subclones in the ascidian Botryllus schlosseri: the resorption phenomenon (Protochordata: Tunicata) , 1987 .

[29]  L W Buss,et al.  Somatic cell parasitism and the evolution of somatic tissue compatibility. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[30]  V. Scofield,et al.  Protochordate allorecognition is controlled by a MHC-like gene system , 1982, Nature.

[31]  I. Weissman,et al.  Stem Cells Are Units of Natural Selection in a Colonial Ascidian , 2006, Cell.

[32]  Richard Astro,et al.  The Log from the Sea of Cortez , 1951 .