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

Weissman, Irving L.

doi:10.1073/pnas.1505464112

Cited by 74 publications

(56 citation statements)

References 32 publications

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“…Our tetrachimeric analysis indicates that a substantial number of progenitors seed the embryonic liver, but fewer remain and contribute to the adult, suggesting clonal selection. We have previously documented cases of stem cell competition (32,33) and here, adult clones differ from fetal clones in vasculature association, suggesting this provides a selective advantage. The data indicate two potential progenitor pools give rise to the adult liver, associated with portal or central veins.…”

Section: Discussionsupporting

confidence: 51%

Localized hepatic lobular regeneration by central-vein–associated lineage-restricted progenitors

Tsai

Koh

Stefanska

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The regeneration of organ morphology and function following tissue loss is critical to restore normal physiology, yet few cases are documented in mammalian postnatal life. Partial hepatectomy of the adult mammalian liver activates compensatory hepatocyte hypertrophy and cell division across remaining lobes, resulting in restitution of organ mass but with permanent alteration of architecture. Here, we identify a time window in early postnatal life wherein partial amputation culminates in a localized regeneration instead of global hypertrophy and proliferation. Quantifications of liver mass, enzymatic activity, and immunohistochemistry demonstrate that damaged lobes underwent multilineage regeneration, reforming a lobe often indistinguishable from undamaged ones. Clonal analysis during regeneration reveals local clonal expansions of hepatocyte stem/progenitors at injured sites that are lineage but not fate restricted. Tetrachimeric mice show clonal selection occurs during development with further selections following injury. Surviving progenitors associate mainly with central veins, in a pattern of selection different from that of normal development. These results illuminate a previously unknown program of liver regeneration after acute injury and allow for exploration of latent regenerative programs with potential applications to adult liver regeneration.n the postnatal liver (1-3), removal of up to 70% of mass results in acute expansion of hepatocytes in remaining lobes to compensate for lost function (4). The classical mechanism is a global program, in which remaining hepatocytes in all lobes hypertrophy, leading to enlargement of cell size and increase in metabolic activity (5). These hepatocytes undergo limited, tightly regulated cell divisions, such that S phase is not always followed by M phase, often generating polyploid hepatocytes, which may later undergo cytokinesis. Lobes subjected to 30% hepatectomy rarely undergo cell division, and compensate primarily by hypertrophy (5). Although total mass and function are restored within 1-2 wk following 70% and 30% hepatectomies, the damaged liver does not regenerate morphology, and instead develops a fibrotic scar that lacks normal cellular composition, with permanent loss of the normal architecture. The absence of regeneration is especially apparent during chronic injury where limited cell divisions and hypertrophy are exhausted by repeated damage.It has been suggested that bipotent hepatic/cholangiocyte stem/ progenitor cells proliferate and differentiate when hepatocyte proliferation is exhausted, as is the case during chronic injury (6-9), although this is controversial (10). Periportal hepatic stem or progenitor cells have been described in response to chemical injury models (11-13). However, to our knowledge, no known progenitor regenerating morphology has been reported after acute damage.Whereas studies of liver development and homeostasis have reported that SRY (sex determining region Y)-box 9 (Sox9 + ), leucine-rich repeat-containing G protein coupled r...

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Section: Discussionsupporting

confidence: 51%

Localized hepatic lobular regeneration by central-vein–associated lineage-restricted progenitors

Tsai

Koh

Stefanska

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…It seemed likely that tissue stem cell biology could account for the programmed life span and could reveal the genetic units of intraorganismal natural selection of stem cell lineages (189)(190)(191). These studies were the basis for our experiments to test for a diversity of competing HSCs in aging, a diversity of germline stem cells in testis and ovary development in mice (192), and the concept of clonal competitions in cancers (161,(193)(194)(195)(196)(197)(198)(199).…”

Section: Cancer Stem Cells and The Therapeutics That Come From Them: mentioning

confidence: 99%

“…In fact, our initial comparisons of gene expression arrays of mouse AML LSCs to normal HSCs and of human AML LSCs to HSCs and MPPs have revealed a plethora of epigenetic targets, just like the genomic analyses have revealed recurrent mutations and orders of mutations and pathways served by the mutations in AMLs. Perhaps the most important extrapolation from this study is to the development of all cancers from tissues that contain self-renewing tissue stem cells; insofar as the mutations are mainly not endowing self-renewal, all such cancers should have a stage of precancer progression in the tissue stem cell, giving rise to the clone that adds or retains self-renewal, and that is likely to be in a downstream oligolineage or multipotent progenitor (183,193).…”

Section: Cancer Stem Cells and The Therapeutics That Come From Them: mentioning

confidence: 99%

“…This is a story of a very long trip from tolerance to T and B cell maturation to stem cells. [I have discussed HSCs, but we have also isolated and transplanted human central nervous system stem cells in clinical trials (254); we have isolated a number of other tissue and cancer stem cells (124,127,193,(255)(256)(257)(258)(259)(260)(261)(262)(263)(264)(265)(266), and many are in progress to investigational therapies.] It is a story with some cautions about human motivations, commerce, and clinical translation.…”

Section: Cancer Stem Cells and The Therapeutics That Come From Them: mentioning

confidence: 99%

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How One Thing Led to Another

Weissman

2016

Annu. Rev. Immunol.

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I started research in high school, experimenting on immunological tolerance to transplantation antigens. This led to studies of the thymus as the site of maturation of T cells, which led to the discovery, isolation, and clinical transplantation of purified hematopoietic stem cells (HSCs). The induction of immune tolerance with HSCs has led to isolation of other tissue-specific stem cells for regenerative medicine. Our studies of circulating competing germline stem cells in colonial protochordates led us to document competing HSCs. In human acute myelogenous leukemia we showed that all preleukemic mutations occur in HSCs, and determined their order; the final mutations occur in a multipotent progenitor derived from the preleukemic HSC clone. With these, we discovered that CD47 is an upregulated gene in all human cancers and is a “don't eat me” signal; blocking it with antibodies leads to cancer cell phagocytosis. CD47 is the first known gene common to all cancers and is a target for cancer immunotherapy.

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“…Irving Weissman (22) addresses stem cells as units of selection, in particular in the framework of cancer development. An example is taken from the model Botryllus schlosseri (a colonial tunicate).…”

Section: Clonality Cancer and Evolutionmentioning

confidence: 99%