Adult telomerase-positive stem cells (aTPSCs) are a proposed population of endogenous adult stem cells described in the scientific literature. They are reported to reside in connective tissue stroma throughout life and to retain activity of the enzyme telomerase while in an undifferentiated state. History The aTPSC model is attributed to work by Henry E. Young, who began studying tissue repair and regeneration in the 1970s in adult terrestrial salamanders, including Ambystoma annulatum. Later publications proposed that the smallest aTPSCs, (TSCs, 0.1–2 μm), were seen as early as a 4-cell stage morula due to asymmetric division of the blastomeres, and with a similar differentiation potential.

Endogenous aTPSCs have been reported in fifteen different animal species, including amphibians, reptiles such as Komodo dragon, avians such as chickens and wattled cranes, mice, rats, rabbits, cats, dogs, sheep, goats, cows, horses, pigs, spectacled bear, and humans, making them a conserved population of stem cells throughout phylogeny.

Proposed biological characteristics According to published descriptions, undifferentiated aTPSCs retain telomerase activity and are therefore proposed to have prolonged proliferative capacity compared with telomerase-negative progenitor cells. The model contrasts these cells with mesenchymal stem cells (MSCs), which are generally described as adult progenitor cells with limited in vitro expansion capacity. The broader cellular-aging context includes the Hayflick limit, the observation that normal human diploid cells have a finite replicative lifespan in culture. In the aTPSC model, cells are said to lose telomerase enzyme after lineage commitment and to acquire a finite replicative lifespan from that point. Consequently, their biologic clock resets to zero meaning the replacement tissues they generate are essentially biologically young relative to the age of the host.

Proposed hierarchy The literature describes aTPSCs as a continuum of eight subcategories distinguished by size, potency and surface-marker profile.

+ Proposed aTPSC subcategories Subcategory Approximate size Proposed potency Proposed forming capacity Totipotent stem cells (TSCs) 0.1–2.0 μm Totipotent Somatic cells, gametes and nucleus pulposus of the intervertebral disc Halo-like stem cells (HLSCs) >2–4 μm Transitional pluripotent Transitional population between TSCs and PSCs Corona-like stem cells (CLSCs) 4–<6 μm Transitional pluripotent Transitional population between HLSCs and PSCs Pluripotent stem cells (PSCs) 6–8 μm Pluripotent Somatic cells only Germ-layer lineage stem cells (GLSCs) 8–10 μm Transitional Between pluripotency and specialized lineages Ectodermal stem cells (EctoSCs) 10–12 μm Lineage-specific Ectodermal tissues Mesodermal stem cells (MesoSCs) 10–12 μm Lineage-specific Mesodermal tissues Endodermal stem cells (EndoSCs) 10–12 μm Lineage-specific Endodermal tissues

Distribution and activation According to the literature, aTPSCs occur in the interstitial connective tissue stroma of multiple organs and tissues, including skeletal muscle, bone marrow, heart, skin, kidney, spleen, peripheral blood, and brain. They are described as quiescent under normal conditions and as capable of activation following trauma or chronic disease. The proposed mechanism includes symmetric proliferation of maternal cells, release of daughter cells, migration to injured tissue by reverse diapedesis, and responses to local tissue-specific cues, including exosome-associated signals.

Immunophenotype The aTPSC literature describes each proposed subcategory as having a characteristic cluster of differentiation (CD) marker profile.

+ Proposed immunophenotypic profiles Subcategory Reported CD markers Notes TSCs CD66e, CEA-CAM-1 Described as lacking MHC class I HLSCs CD66e high/CD10 low; CEA-CAM-1 high/SSEA-4 low Transitional; described as lacking MHC class I CLSCs CD66e low/CD10 high; CEA-CAM-1 low/SSEA-4 high Transitional; described as lacking MHC class I PSCs CD10, SSEA-4 Described as lacking MHC class I GLSCs CD10 high/CD90 low; SSEA-4 high/Thy-1 low Described as lacking MHC class I EctoSCs CD56, CD90/Thy-1, MHC class I MHC class I reported MesoSCs CD13, CD90/Thy-1, MHC class I MHC class I reported EndoSCs CD90/Thy-1, MHC class I MHC class I reported

The absence of MHC class I on the more primitive proposed populations suggests that some aTPSC subcategories may have allogeneic applications, whereas lineage-specific cells expressing MHC class I would not be expected to share the same immunological profile.

Therapeutic claims There are published reports describing autologous and allogeneic use of telomerase-positive stem cells in chronic diseases and traumatic injuries, including osteoarthritis, systemic lupus erythematosus, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, celiac disease, cardiovascular disease, age-related macular degeneration, Alzheimer's disease, visual impairment, spinal-cord injury, chronic inflammatory demyelinating polyneuropathy and Parkinson disease. The cited reports state that these studies involved 96 individuals and 20 chronic diseases or traumatic injuries, with a reported 100% safety record and cumulative efficacy of 86.4%. These figures should be treated as claims from the cited aTPSC literature rather than independently established clinical consensus.

Controversy and criticism Concerns have been raised about the reliability and reproducibility of the reported isolation protocols. The methods described by Young and collaborators differ from standard protocols used for differentiated cells, progenitor cells, MSCs, iPSCs and ESCs. Young has argued that aTPSCs constitute a distinct cell population and therefore require distinct processing and culture methods.

See also Adult stem cell Stem cell Telomerase Mesenchymal stem cell Induced pluripotent stem cell Embryonic stem cell Regenerative medicine

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