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.”

A Simplified and Effective Approach for the Isolation of Small Pluripotent Stem Cells Derived from Human Peripheral Blood

“…Our approach results in the isolation of a rich population of SBSCs, with various characteristics, as some of them expressed all the widely studied pluripotent stem cell markers (KP-1, Nanog, Oct4, SOX-2, cMyc, KLF4, CXCR4, SSEA-3 and SSEA-4), other certain hematopoietic markers (CD90, CD133 and CD45) and portions of them being mesenchymal markers (CD29, PTH1R, CD105 and CD106). Therefore, we show that the isolated SBSCs consist of a mixed pluripotent population of stem cells that includes a fraction with mesenchymal and hematopoietic characteristics, aligning with previous studies supporting the heterogeneous character of small stem cells in the cord blood [ 66 , 67 , 68 ].…”

Identification and quantification of very small embryonic-like (VSEL) stem cells in fresh umbilical cord blood

“…The existence of VSELs has been heavily debated ever since they were first reported [8]. The main reason for the scepticism surrounding these cells is that there is a lack of standardisation regarding the markers used for phenotyping VSELs.…”

“…This population has since gained significant interest due to its ability to give rise to all three germ cell layers combined with its lack of tumourogenicity [5,6,7]. It has therefore been proposed as a promising cell source for tissue regeneration [8].…”

Standardisation is the key to the sustained, rapid and healthy development of stem cell‐based therapy

“…ASC‐based therapies have a wide range of clinical applications, covering the treatment of diseases in cardiovascular, orthopaedic, autoimmune, neurological, metabolic and other systems 3,98 . As PSCs, VSELs constitute a recruitable stem cell pool and can also play an important role in tissue repair 46,99 . Studies have found that VSELs in patients with lung disease can be recruited into peripheral blood (PB) to participate in tissue repair 46 .…”