Universal patterns of stem cell fate in cycling adult tissues.
TL;DR: It is proposed that tissue stem cells are routinely lost and replaced in a stochastic manner, and the concept of the stem cell as an immortal, slow-cycling, asymmetrically dividing cell is challenged.
Abstract: In cycling tissues that exhibit high turnover, tissue maintenance and repair are coordinated by stem cells. But, how frequently stem cells are replaced following differentiation, aging or injury remains unclear. By drawing together the results of recent lineage-tracing studies, we propose that tissue stem cells are routinely lost and replaced in a stochastic manner. We show that stem cell replacement leads to neutral competition between clones, resulting in two characteristic and recurring patterns of clone fate dynamics, which provide a unifying framework for interpreting clone fate data and for measuring rates of stem cell loss and replacement in vivo. Thus, we challenge the concept of the stem cell as an immortal, slow-cycling, asymmetrically dividing cell.
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TL;DR: The widespread importance of Wnt signaling in driving tissue renewal has been revealed by the identification of Axin2 and Lgr5, genes expressed in cells that are responding to Wnt signals, and this crucial role in stem cell self renewal is reviewed.
Abstract: BACKGROUND In adult mammalian organisms, multiple tissues—including the skin, blood, stomach, and intestines—are entrapped in a state of permanent regeneration; older cells are constantly shed, and the tissue is continuously being regenerated from resident stem cells. This phenomenon of “tissue renewal” was appreciated by Leblond in 1956, but the underlying mechanism has been unclear. It is now evident that a class of extracellular developmental signaling proteins, known as Wnt signals, animate the continued renewal of several mammalian tissues by fuelling stem cell activity. If the Wnt pathway is inhibited, tissue renewal is crippled. This signaling pathway is an ancient evolutionary program dating from when Wnt signals arose in the simplest multicellular organisms, in which Wnts acted as primordial symmetry-breaking signals crucial for the generation of patterned tissues during embryogenesis. In vertebrates, these signals also function in pattern maintenance: They sustain tissue renewal, enabling tissues to be continuously replenished and maintained over a lifetime. Multiple adult organs are in a state of continual regeneration. In tissues such as the skin, intestines, brain, and mammary glands, Wnt signaling proteins sustain this constant regeneration by inducing stem cells (green cells in the illustration) to grow. This leads to the robust supply of new cells (green) in order to replenish and maintain the tissue. [Image credits are available in the full article online.] ADVANCES In contrast to traditional “long-range” developmental signals, Wnts seem to act as short-range intercellular signals—acting mostly between adjacent cells. Lending credence to this notion, a membrane-tethered Wnt protein variant can fulfill most functions of a normal Wnt protein in Drosophila . Likely explaining the short-range nature of these signals, Wnt proteins are attached to a lipid and therefore are hydrophobic; they cannot freely traverse the extracellular space by themselves. This provides insight into how tissue renewal is regulated. It implies that Wnt signals emanating from the stem cell microenvironment (the “niche”) may influence adjacent stem cells without affecting a broad field of cells located farther away. The concept of an external niche, however, may have to be refined because it is clear that stem cells can sometimes act as their own niche and have unexpected developmental self-organizing capacities. Last, the widespread importance of Wnt signaling in driving tissue renewal has been revealed by the identification of Axin2 and Lgr5 , genes expressed in cells that are responding to Wnt signals. Genetically labeling Axin2 + or Lgr5 + cells in a variety of tissues has revealed that such cells fuel tissue renewal in the intestines, mammary gland, skin, and brain, among other organs. OUTLOOK The amazing continuous self-regeneration of various mammalian tissues over years and decades continues to be an enigmatic terra incognita in biology. For instance, visualization of stem cells in real-time in vivo (through intravital microscopy) has shown that when some stem cells are ablated, they are replaced by more differentiated cells that are recalled to the stem cell niche, whereupon they regain stem cell identity to effect tissue repair. Therefore, lineage barriers between stem cell and differentiated fates are not always stringent and can be traversed during times of tissue damage. Reactivated Wnt signals may be instrumental in this process, and perhaps such signals could be exploited in order to enkindle tissue regeneration after injury or disease. From a pragmatic perspective, Wnt signals have already found practical use in manipulating stem cells, enabling propagation of stem cells in vitro as self-renewing cell populations and as organoids.
1,032 citations
TL;DR: Surprisingly, it is found that the majority of labelled tumour cells in benign papilloma have only limited proliferative potential, whereas a fraction has the capacity to persist long term, giving rise to progeny that occupy a significant part of the tumour.
Abstract: Recent studies using the isolation of a subpopulation of tumour cells followed by their transplantation into immunodeficient mice provide evidence that certain tumours, including squamous skin tumours, contain cells with high clonogenic potential that have been referred to as cancer stem cells (CSCs). Until now, CSC properties have only been investigated by transplantation assays, and their existence in unperturbed tumour growth is unproven. Here we make use of clonal analysis of squamous skin tumours using genetic lineage tracing to unravel the mode of tumour growth in vivo in its native environment. To this end, we used a genetic labelling strategy that allows individual tumour cells to be marked and traced over time at different stages of tumour progression. Surprisingly, we found that the majority of labelled tumour cells in benign papilloma have only limited proliferative potential, whereas a fraction has the capacity to persist long term, giving rise to progeny that occupy a significant part of the tumour. As well as confirming the presence of two distinct proliferative cell compartments within the papilloma, mirroring the composition, hierarchy and fate behaviour of normal tissue, quantitative analysis of clonal fate data indicates that the more persistent population has stem-cell-like characteristics and cycles twice per day, whereas the second represents a slower cycling transient population that gives rise to terminally differentiated tumour cells. Such behaviour is shown to be consistent with double-labelling experiments and detailed clonal fate characteristics. By contrast, measurements of clone size and proliferative potential in invasive squamous cell carcinoma show a different pattern of behaviour, consistent with geometric expansion of a single CSC population with limited potential for terminal differentiation. This study presents the first experimental evidence for the existence of CSCs during unperturbed solid tumour growth.
698 citations
TL;DR: It is shown that combinatorial, cumulative genome editing of a compact barcode can be used to record lineage information in multicellular systems and that rich, systematically generated maps of organismal development will advance the understanding of development in both healthy and disease states.
Abstract: Multicellular systems develop from single cells through distinct lineages. However, current lineage-tracing approaches scale poorly to whole, complex organisms. Here, we use genome editing to progressively introduce and accumulate diverse mutations in a DNA barcode over multiple rounds of cell division. The barcode, an array of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 target sites, marks cells and enables the elucidation of lineage relationships via the patterns of mutations shared between cells. In cell culture and zebrafish, we show that rates and patterns of editing are tunable and that thousands of lineage-informative barcode alleles can be generated. By sampling hundreds of thousands of cells from individual zebrafish, we find that most cells in adult organs derive from relatively few embryonic progenitors. In future analyses, genome editing of synthetic target arrays for lineage tracing (GESTALT) can be used to generate large-scale maps of cell lineage in multicellular systems for normal development and disease.
570 citations
TL;DR: It is found that CH is very common in the elderly, trending toward inevitability, and somatic mutations in TET2, DNMT3A, ASXL1, and PPM1D are associated with CH at high significance, however, known CD mutations were evident in only a fraction of CH cases.
549 citations
TL;DR: Quantitative analysis of clonal fate data and proliferation dynamics demonstrate the existence of two distinct proliferative cell compartments arranged in a hierarchy involving slow-cycling stem cells and committed progenitor cells in the skin interfollicular epidermis.
Abstract: The skin interfollicular epidermis (IFE) is the first barrier against the external environment and its maintenance is critical for survival. Two seemingly opposite theories have been proposed to explain IFE homeostasis. One posits that IFE is maintained by long-lived slow-cycling stem cells that give rise to transit-amplifying cell progeny, whereas the other suggests that homeostasis is achieved by a single committed progenitor population that balances stochastic fate. Here we probe the cellular heterogeneity within the IFE using two different inducible Cre recombinase–oestrogen receptor constructs targeting IFE progenitors in mice. Quantitative analysis of clonal fate data and proliferation dynamics demonstrate the existence of two distinct proliferative cell compartments arranged in a hierarchy involving slow-cycling stem cells and committed progenitor cells. After wounding, only stem cells contribute substantially to the repair and long-term regeneration of the tissue, whereas committed progenitor cells make a limited contribution.
501 citations
References
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Book•
01 Jan 1983
TL;DR: The neutral theory as discussed by the authors states that the great majority of evolutionary changes at the molecular level are caused not by Darwinian selection but by random drift of selectively neutral mutants, which has caused controversy ever since.
Abstract: Motoo Kimura, as founder of the neutral theory, is uniquely placed to write this book. He first proposed the theory in 1968 to explain the unexpectedly high rate of evolutionary change and very large amount of intraspecific variability at the molecular level that had been uncovered by new techniques in molecular biology. The theory - which asserts that the great majority of evolutionary changes at the molecular level are caused not by Darwinian selection but by random drift of selectively neutral mutants - has caused controversy ever since. This book is the first comprehensive treatment of this subject and the author synthesises a wealth of material - ranging from a historical perspective, through recent molecular discoveries, to sophisticated mathematical arguments - all presented in a most lucid manner.
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01 Jan 1981
TL;DR: In this article, the authors introduce the Fokker-planck equation, the Langevin approach, and the diffusion type of the master equation, as well as the statistics of jump events.
Abstract: Preface to the first edition. Preface to the second edition. Abbreviated references. I. Stochastic variables. II. Random events. III. Stochastic processes. IV. Markov processes. V. The master equation. VI. One-step processes. VII. Chemical reactions. VIII. The Fokker-Planck equation. IX. The Langevin approach. X. The expansion of the master equation. XI. The diffusion type. XII. First-passage problems. XIII. Unstable systems. XIV. Fluctuations in continuous systems. XV. The statistics of jump events. XVI. Stochastic differential equations. XVII. Stochastic behavior of quantum systems.
7,858 citations
Book•
31 Dec 1985
TL;DR: The construction, and other general results are given in this paper, with values in [0, ] s. The voter model, the contact process, the nearest-particle system, and the exclusion process.
Abstract: The Construction, and Other General Results.- Some Basic Tools.- Spin Systems.- Stochastic Ising Models.- The Voter Model.- The Contact Process.- Nearest-Particle Systems.- The Exclusion Process.- Linear Systems with Values in [0, ?)s.
4,365 citations
"Universal patterns of stem cell fat..." refers background in this paper
...…by treatments in which labelled and unlabelled stem cells represent voters with different political opinions) a ‘voter model’ (Holley and Liggett, 1975), which has received much attention from both mathematicians and physicists (Ben-Naim et al., 1996; Liggett, 1985; Sood and Redner, 2005)....
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TL;DR: It is stated that these sequences differed in the cytochromes c of various species to an extent that seemed unnecessary from the standpoint of their function.
Abstract: IN 1966, I became interested in the amino acid sequences of cytochrome c molecules ([Jukes 1966][1]). I noted that these sequences differed in the cytochromes c of various species to an extent that seemed unnecessary from the standpoint of their function. I stated, “The changes produced in
3,011 citations
"Universal patterns of stem cell fat..." refers background in this paper
...Perhaps the best-known example of these games in biology is the neutral theory of molecular evolution in population genetics (Kimura, 1983), which proposes that competition between alleles of equal fitness leads to ‘neutral drift’ of the alleles within a population....
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3,009 citations
"Universal patterns of stem cell fat..." refers background in this paper
...Cell-autonomous self-renewal In this scenario, cell fate is specified randomly with each stem cell division leading to stem cell multiplication or loss with equal probability [a mathematical process known as a critical birth-death process (Bienayme, 1845; Harris, 1948; van Kampen, 2007)]....
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