Toward a new paradigm of cell plasticity

Abstract

The standard paradigm of embryologic development and adult tissue reconstitution posits unidirectional, hierarchical lineages. The presumed mechanisms underlying these differentiative pathways are gene restrictions, such as methylation and heterochromatin formation, which are commonly described as irreversible. However, recent discoveries regarding multi-organ stem cells demonstrate that 'true plasticity' exists, with cells of one organ turning into cells of other organs, including differentiative transformations that cross barriers between tissues derived from different primitive germ layers. These findings, along with earlier experiments into heterokaryon formation and longstanding recognition of reactive and neoplastic lesions in humans and animals, suggest that lineage pathways are not, in fact, unidirectional. Moreover, physiologic mechanisms of reversal of gene restrictions have been recognized. Therefore, in response to these observations, we suggest a new paradigm of cell plasticity, elucidating three guiding principles of 'genomic completeness', 'uncertainty of cell characterization', and 'stochastic nature of cell origins and fates'. These principles imply a change in the way data can be interpreted and could alter subsequent hypothesis formation. This new paradigm will hopefully lead us forward to a more flexible and creative exploration of the potential of adult vertebrate cells.

Implications of ‘postmodern biology' for pathology: the Cell Doctrine

“…The similarity of this idea to Heisenberg's Uncertainty Principle from quantum mechanics led to our designating this second principle as 'cellular uncertainty'. [14][15][16] However, approximately a decade before we published on this concept, it had been proposed by Chris Potten and Markus Loeffler, arrived at through their collaborative work in mathematical and computer modeling of stem cell processes of the small intestine. 18 Quantum 'uncertainty' was first thought, even by Heisenberg himself, as perhaps merely a limitation of technological innovation for examination of subatomic particles, but eventually was revealed to be an irreducible feature of universal structure.…”

“…[14][15][16] The first principle is referred to as the principle of 'genomic completeness'. With cloning as proof-of-principle, supported by an ever-expanding demonstration of the reversibility of gene restrictions described above, one may state that 'any cell which has the entire genome intact can become any other cell type'.…”

“…These mechanical interventions have been demonstrated to alter cell behavior. 15 How much more so will mechanical and/ or enzymatic tissue disaggregation, violently breaking cell:cell and cell:matrix linkages, alter the behavior of a cell? It is disingenuous at best to assume that these are simply 'neutral' isolation steps.…”

“…In other words, cellular heterogeneity is irreducible, and descriptions of the cell populations must be expressed in terms of probabilities. 15,16 The third principle is accordingly designated the 'stochasticity of cell fate'.…”

“…However, considering genomic completeness and cellular uncertainty in light of each other, one is logically required to then state that cell lineages, to the best that we can observe them, are stochastic processes and that to describe the progenitors or progeny of any given cell under observation, one must speak in terms of probabilities. [14][15][16] Moreover, in describing a population of cells, there must be recognition of inherent variation, no matter how well characterized the population. In other words, cellular heterogeneity is irreducible, and descriptions of the cell populations must be expressed in terms of probabilities.…”