Novel Insights into Adult and Cancer Stem Cell Biology

Abstract

Adult tissues are thought to harbor two populations of "dormant" and "actively dividing" stem cells. Quiescent stem cells undergo rare asymmetric cell divisions (ACDs) through which they self-renew and give rise to tissue-committed "progenitors" of distinct fate and "progenitors" in turn undergo symmetric cell divisions (SCDs) and clonal expansion. However, quiescent stem cells have not been demonstrated in adult tissues such as skin, testis, liver, and brain. After surgical removal of part of liver and pancreas-adult differentiated cells divide and regenerate and a possible role of stem cells remains doubtful. Long-term repopulating hematopoietic stem cells are quiescent in nature but ACD has not been convincingly demonstrated even among them. Attempts by various groups to identify a common stemness program that ensures self-renewal among different kinds of stem cells have also remained futile. Uncontrolled self-renewal and compromised differentiation of stem cells possibly initiate leukemia/cancer, but the identity of leukemic stem cells and whether cancer stem cells arise by epithelial-mesenchymal transition (EMT) in solid tumors are all open-ended questions that need greater clarity. Acceptance of the presence of very small embryonic-like stem cells (VSELs) in adult tissues could clarify several of these existing dilemmas in the field. Data are compiled showing that VSELs undergo ACD in the hematopoietic system, testis, ovary, uterus, and pancreas, whereas tissue-committed progenitors undergo SCD and clonal expansion. VSELs possess similar overlapping stemness program as in embryonic stem cells, embryonic carcinoma cells, embryonic germ cells, induced pluripotent stem cells, and primordial germ cells. VSELs and leukemic and cancer cells express overlapping embryonic markers. Uncontrolled proliferation of VSELs and compromised differentiation possibly initiate leukemia. Process of EMT and initiation of solid tumor from VSELs (located among the epithelial cells) are indeed two distinct and parallel events. To conclude, VSELs provide explanation to several confounding aspects of adult stem cell biology.

<p>Role of Stem-Cell Transplantation in Leukemia Treatment</p>

“…They differentiate into HSCs in vitro. 23 VSELSCs can be generated from primordial germ cells and undergo further differentiation into HSCs 47 ( Figure 1 ). Bone marrow–derived VSELSCs may not have features characteristic of hematopoietic progenitor SCs, but they can retain hematopoietic features through external-stress growth factors.…”

“…Allo-HSCT has also been used as a treatment option for acute lymphoid leukemia and multiple myeloma. 1 , 23 , 94 Though alternative treatments remain undefined, it is a valuable treatment tool for hematologic malignancies. Reduced-intensity conditioning after allo-HSCT has been seen in Spain.…”

“…22 They differentiate into HSCs in vitro. 23 With specific forward reprogramming protocols, induced pluripotent SCs (iPSCs) have therapeutic potential to generate hemato-endothelial progenitor (HEP) cells.…”

Stem cells survive oncotherapy & can regenerate non-functional gonads

“…VSELs in chemoablated mouse testis increased in numbers after FSH treatment and this action was possibly mediated through FSHR3. ( iii ) VSELs were found to undergo self-renewal and asymmetric cell division and considered the most primitive stem cells in the testis 38 54 . Thus, the most primitive stem cells in the testes 55 that undergo self-renewal and give rise to SSCs might be VSELs.…”

“…These stem cells have been labelled differently by various investigators and have remained elusive over decades due to their small size and presence in very few numbers 37 . VSELs are the most primitive, pluripotent stem cells in the adult organs and give rise to tissue-specific stem cells by undergoing rare asymmetrical cell divisions to self-renew and give rise to slightly bigger tissue-committed adult stem cells ‘progenitors’ 38 . The tissue committed adult stem cells or ‘progenitors’ in turn undergo symmetrical cell divisions, clonal expansion and further differentiation into tissue-specific cell types.…”