Very small embryonic-like stem cells have the potential to win the three-front war on tissue damage, cancer, and aging

Abstract

The concept of dedifferentiation and reprogramming of mature somatic cells holds much promise for the three-front "war" against tissue damage, cancer, and aging. It was hoped that reprogramming human somatic cells into the induced pluripotent state, along with the use of embryonic stem cells, would transform regenerative medicine. However, despite global efforts, clinical applications remain a distant dream, due to associated factors such as genomic instability, tumorigenicity, immunogenicity, and heterogeneity. Meanwhile, the expression of embryonic (pluripotent) markers in multiple cancers has baffled the scientific community, and it has been suggested that somatic cells dedifferentiate and "reprogram" into the pluripotent state in vivo to initiate cancer. It has also been suggested that aging can be reversed by partial reprogramming in vivo. However, better methods are needed; using vectors or Yamanaka factors in vivo, for example, is dangerous, and many potential anti-aging therapies carry the same risks as those using induced pluripotent cells, as described above. The present perspective examines the potential of endogenous, pluripotent very small embryonic-like stem cells (VSELs). These cells are naturally present in multiple tissues; they routinely replace diseased tissue and ensure regeneration to maintain life-long homeostasis, and they have the ability to differentiate into adult counterparts. Recent evidence suggests that cancers initiate due to the selective expansion of epigenetically altered VSELs and their blocked differentiation. Furthermore, VSEL numbers have been directly linked to lifespan in studies of long- and short-lived transgenic mice, and VSEL dysfunction has been found in the ovaries of aged mice. To conclude, a greater interest in VSELs, with their potential to address all three fronts of this war, could be the "light at the end of the tunnel."

Keywords: VSELs; cancer; iPS cells; regeneration; stem cells.

FIGURE 1

(A) compares VSELs with ES and iPS cells. Pluripotent VSELs exist in adult tissues; they regularly participate in adult tissue regeneration and remodeling, with no risk of teratoma formation. More focused research efforts are required to make use of their regenerative potential. (B) shows that VSELs sit at the top of the hematopoietic system hierarchy, and that they give rise to HSCs, MSCs, and EPCs. VSELs, very small embryonic-like stem cells; ES cells, embryonic stem cells; iPS cells, induced pluripotent stem cells; HSCs, hematopoietic stem cells; MSCs, mesenchymal stem cells; EPCs, endothelial progenitor cells.

FIGURE 2

VSELs have the potential to win the war for human health on three major fronts. As shown, VSELs have the ability to regenerate adult tissues with none of the associated problems currently facing human embryonic and induced pluripotent stem cells, including ethical concerns as well as genomic instability, tumorigenicity, immunogenicity, and heterogeneity. Age-related disorders occur due to VSEL dysfunction. Various pathologies, including cancer, occur due to the dysfunction of the stem/progenitor cell compartment in adult tissues, as shown in the bottom panel. Excessive self-renewal of VSELs results in cancer, and the blocking of stem/progenitor cells differentiation (to different extents) gives rise to a wide spectrum of pathologies. This was first revealed through studying the effects of neonatal exposure to endocrine disruption on mouse reproductive tissues, but similar mechanisms could exist in other organs as well. More focused research on various aspects of VSELs is needed. VSELs, very small embryonic-like stem cells; PGCs, primordial germ cells; TCSCs, tissue-committed stem cells (progenitors); ACD, asymmetrical cell division; SCD, symmetrical cell division.