The chiaroscuro stem cell: a unified stem cell theory

Abstract

Hematopoiesis has been considered hierarchical in nature, but recent data suggest that the system is not hierarchical and is, in fact, quite functionally plastic. Existing data indicate that engraftment and progenitor phenotypes vary inversely with cell cycle transit and that gene expression also varies widely. These observations suggest that there is no progenitor/stem cell hierarchy, but rather a reversible continuum. This may, in turn, be dependent on shifting chromatin and gene expression with cell cycle transit. If the phenotype of these primitive marrow cells changes from engraftable stem cell to progenitor and back to engraftable stem cell with cycle transit, then this suggests that the identity of the engraftable stem cell may be partially masked in nonsynchronized marrow cell popula- IntroductionWe present here a different view of early hematopoiesis. This is not the standard dogma of many investigators in the field, but is built upon solid work by many laboratories over many years. This is a perspective, and thus naturally reflects the biases of the authors. These, in turn, have a basis in many published studies from our laboratory and other laboratories and also from extensive unpublished, but abstracted, data from our laboratory. It is appropriate to consider this contribution as speculative in nature.The term chiaroscuro refers to the treatment of light and shade in painting. Our current view of the changing phenotype of the marrow stem cell suggests a chiaroscuro nature to this picture.In general, models of stem cell regulation have been hierarchical. 1,2 A primitive stem cell, with great potential, gives rise to a proliferating progenitor pool, which in turn gives rise to recognizable differentiated cells. During this process, proliferative potential is lost, while specific differentiated features are acquired. Presumptively, but without definite proof, there is also self-renewal at the most primitive stem cell level, and this is also lost with differentiation. Many data exist to support such a hierarchical model. Marrow cells have been separated with short-and long-term repopulation potential 3,4 and progenitors have been characterized as exclusively committed to the production of restricted progeny. 5,6 In addition, the clear expansion of different progenitor types in cytokinestimulated in vitro culture with a loss of long-term engraftment capacity speaks to the existence of a progenitor hierarchy, at least at the more differentiated progenitor levels. 7,8 A model encompassing these features is shown in Figure 1.This model does not fit with all published data. For instance, the "daughter cell" or paired-progenitor experiments of Suda and colleagues 9 indicate that a primitive progenitor cell can make totally different lineage choices during one cell cycle transit, such that, for example, one daughter cell forms an erythroid colony while the other daughter (or sister) cell forms a neutrophilmacrophage colony. Out of a total of 387 pairs evaluated, 68 pairs of colonies consisted of dissimilar com...

Correlation between differentiation plasticity and mRNA expression profiling of CD34+-derived CD14− and CD14+ human normal myeloid precursors

“…As recently reviewed, 'polymerase accessibility to chromatin is a limiting step for both RNA and DNA synthesis'. 28 For this reason, it is generally believed that chromatin remodeling, RNA transcription, DNA replication and, consequently, cell cycle control are strictly coordinated processes sharing molecular components and probably subnuclear localization. 'chromatin remodeling associated with cell cycle transit' is responsible for the differentiation potentiality of hematopoietic stem/progenitor cells.…”

“…6,27,28 Based on this premise, we assessed whether the expression pattern of the main chromatin remodeling complexes [27][28][29] could explain the different maturation plasticity of analyzed cell populations. As reported in Figure 5, panel a, five different chromatin regulators belonging to the SWI/SNF ATPase family (SMARCA3, SMARCC1, SMARCE1, CHD4, CHD1L), the HDAC1 deacetylase, the MORF acetyl-transferase, two methyl-lysine binding proteins (HP1, CBX5) and the DNA methyl-transferase 3 B exhibited a downregulated expression in CD14 þ monocyte precursors.…”

Transdetermination: Drosophila imaginal disc cells exhibit stem cell-like potency

“…Such cell-cycle changes may allow for transcriptional reprogramming and TD. This idea is based on the fact that as stem cells progress through the cell cycle their decision to become a stem cell or commit to a particular lineage is most vulnerable during S phase, when there are dramatic structural changes made to the chromatin, resulting in numerous transcriptional changes (Holtzer et al, 1975;Quesenberry, Colvin, & Lambert, 2002).…”

The GOD of Hematopoietic Stem Cells: A Clonal Diversity Model of the Stem Cell Compartment

“…These hypothesize respectively that HSC behavior is either not predictable (stochastic) or predictable (deterministic). [20][21][22][23][24][25][26] For a comprehensive overview of models see the review by Viswanathan and Zandstra. 27 Without fail, all currently accepted theories assume the existence of a single type of mother-of-all-HSC (or most primitive HSC) in adult bone marrow (BM).…”