A revisionist history of adult marrow stem cell biology or ‘they forgot about the discard’

Abstract

The adult marrow hematopoietic stem cell biology has largely been based on studies of highly purified stem cells. This is unfortunate because during the stem cell purification the great bulk of stem cells are discarded. These cells are actively proliferating. The final purified stem cell is dormant and not representative of the whole stem cell compartment. Thus, a large number of studies on the cellular characteristics, regulators and molecular details of stem cells have been carried on out of non-represented cells. Niche studies have largely pursued using these purified stem cells and these are largely un-interpretable. Other considerations include the distinction between baseline and transplant stem cells and the modulation of stem cell phenotype by extracellular vesicles, to cite a non-inclusive list. Work needs to proceed on characterizing the true stem cell population.

Differentiation Epitopes Define Hematopoietic Stem Cells and Change with Cell Cycle Passage

“…We have developed a continuum model of hematopoiesis in which the stem cell phenotype is continually changing on a cell cycle related basis, with fluctuations in self-renewal potential and lineage fate linked to cell cycle transit [ 11 – 13 ]. The work presented here indicates that c-Kit, Sca-1 and CD150 are likely reliable stem cell epitopes and may define the true hematopoietic stem cell population, but that a significant portion of this population is actively cycling and may have fluctuating expression of lineage specific epitopes and therefore be at risk of discard during lineage depletion.…”

Heuristic bias in stem cell biology

“…Studying purified lineage-negative, rhodamine-low, Hoechst-low stem cells traversing cell cycle, synchronized under cytokine stimulation, we have also shown virtually total heterogeneity at different points in cell cycle [3]. This all leads up to the real shocker: the purified hematopoietic stem cell, which has been so heavily studied, is not representative of the total population of hematopoietic stem cells, at least in murine studies [4, 5]. The population of stem cells which exist in whole marrow is actively cycling, always changing, and cannot be “purified” by current standard epitope selection approaches.…”

Mesenchymal stromal/stem cells: historical perspective and ongoing challenges

“…Adult stem cells were defined in the XX century as a cell population able to self-renew and to give rise to specific tissue differentiated cells, replenishing lost cells. Currently, it is well agreed that almost all adult tissues contain a stem cell population that reside in specific microenvironments (the stem cell niche) and give rise to downstream committed progenitors that generate terminally differentiated cells (Clevers, 2015;Ferraro et al, 2010;Morrison & Spradling, 2008;Post & Clevers, 2019;Quesenberry & Goldberg, 2017;Slack, 2018). The concept of a stem cell-based unidirectional hierarchical organization of tissues has its roots in studies about the reconstitution of the hematopoietic tissue.…”

“…Stem cell division seems to be driven by tissue-specific demands under physiological or pathological conditions, which means that in some tissues, as in the gut, stem cells are neither rare nor quiescent. Moreover, some plasticity of the unidirectional differentiation of progenitors was observed (Clevers, 2015;Klein & Simons, 2011;Post & Clevers, 2019;Quesenberry & Goldberg, 2017;Slack, 2018). So, what makes a cell a stem cell?…”

“…So, what makes a cell a stem cell? A broad definition of stem cells as cells capable to replenish lost tissues, whose properties are controlled by their microenvironment has been proposed, based on data from murine models (Guiu et al, 2019;Post & Clevers, 2019;Quesenberry & Goldberg, 2017). Further investigations are needed in order to confirm whether this statement can be widely applied.…”