The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index; none of the 30 sources its claims cite is checked for support yet.
Conditional telomerase induction causes proliferation of hair follicle stem cells
Open accessAbstract
TERT, the protein component of telomerase, serves to maintain telomere function through the de novo addition of telomere repeats to chromosome ends, and is reactivated in 90% of human cancers. In normal tissues, TERT is expressed in stem cells and in progenitor cells, but its role in these compartments is not fully understood. Here we show that conditional transgenic induction of TERT in mouse skin epithelium causes a rapid transition from telogen (the resting phase of the hair follicle cycle) to anagen (the active phase), thereby facilitating robust hair growth. TERT overexpression promotes this developmental transition by causing proliferation of quiescent, multipotent stem cells in the hair follicle bulge region. This new function for TERT does not require the telomerase RNA component, which encodes the template for telomere addition, and therefore operates through a mechanism independent of its activity in synthesizing telomere repeats. These data indicate that, in addition to its established role in extending telomeres, TERT can promote proliferation of resting stem cells through a non-canonical pathway.
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TL;DR
Conditional transgenic induction of TERT in mouse skin epithelium is sufficient to drive the telogen-to-anagen transition of the hair follicle cycle and promote hair growth by causing proliferation of quiescent bulge stem cells. This activity does not require TERC and therefore operates independently of telomere synthesis.
Key findings
- Doxycycline-induced TERT expression in i-TERT mice kept hair follicles in anagen at day 50, whereas i-TERT mice off doxycycline and non-transgenic mice had exited to telogen; the effect occurred with 100% penetrance (18/18 in anagen; chi-square p<0.0001 for i-TERT on vs. off doxycycline).
- Inducing TERT after follicles had entered the prolonged second telogen (day 40) drove anagen entry by day 9 and mid-anagen by day 12 (p=0.005), and doxycycline-treated i-TERT mice shaved at day 55 showed significant hair growth at 14 days versus controls, which showed none.
- TERT caused proliferation of quiescent bulge stem cells: BrdU label in CD34+ bulge cells was depleted by 76% (BrdU+ cells/CD34+ cell, p<0.0001) after five weeks of doxycycline, while CD34+ cell numbers remained similar, suggesting division with self-renewal.
- The effect is TERC-independent: conditional TERT activation induced anagen in 5/5 i-TERT;TERC−/− mice (p=0.0003 vs. i-TERT off doxycycline), identical to TERC+/+ and TERC+/− backgrounds (6/6 in anagen), despite confirmed absence of telomerase activity and TERC RNA.
- Effects were epithelium-intrinsic: K5-tTA+;tetop-TERT+ mice showed anagen in 5/5 versus telogen in 6/6 littermate controls (p=0.0009), and interfollicular epidermal proliferation was unchanged (4.2 Ki-67+ cells/100μm in i-TERT day 50 vs. 4.3 in non-transgenic day 28).
Methods
- Conditional tetracycline-regulated transgenic system: mouse TERT cDNA under a tetracycline-responsive promoter (tetop-TERT) crossed with actin-rtTA mice to generate inducible TERT (i-TERT) mice, with doxycycline administered in drinking water; a K5-tTA;tetop-TERT cross (tet-off) restricted expression to the basal layer/outer root sheath.
- Telomerase activity and expression assessed by TRAP assay, Northern blot, RT-PCR, and RNA in situ hybridization; hair cycle stage assessed by H&E histology of dorsal skin biopsies.
- Bulge stem cells marked by repeated BrdU injections at 10 days of age followed by a long chase (45–90 days) and visualized by BrdU/CD34 double immunofluorescence on sections and tail epidermal wholemounts; TERC+/− mice backcrossed to FVB/N for six generations were intercrossed to yield TERC+/+, +/−, and −/− i-TERT cohorts.
Limitations
- The paper states that in this transgenic context "either altered timing of TERT expression or higher protein levels may be important in mediating these new activities for TERT," and calls for loss-of-function studies and experiments to determine whether TERT's function in stem cell proliferation is cell autonomous.
- Evident from the text: the conclusions rest on transgenic TERT overexpression rather than endogenous TERT, so the physiological relevance of the non-canonical activity is not established here.
- Evident from the text: mechanistic details of the TERC-independent pathway are not identified, and the work is confined to mouse skin/hair follicle biology.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“TERT mRNA and telomerase activity progressively increased from day 3 through day 9 (Fig 2a).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Remarkably, within several weeks of doxycycline treatment, the coats of i-TERT mice were significantly altered, reminiscent of mice with known mutations that affect hair follicle cycling26,27 (Fig 1e).”
What the sources say
- Not checked yetcites [26] Hebert, J. M., Rosenquist, T., Gotz, J. & Martin, G. R. FGF5 as a regulator of the hair growth cycle: evidence from targeted and spontaneous mutations. Cell 78, 1017–1025 (1994) source
- Not checked yetcites [27] Gat, U., DasGupta, R., Degenstein, L. & Fuchs, E. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell 95, 605–614 (1998) source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we show that conditional transgenic induction of TERT in mouse skin epithelium causes a rapid transition from telogen, the resting phase of the hair follicle cycle, to anagen, the active phase, thereby facilitating robust hair growth.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This new function for TERT does not require the telomerase RNA component (TERC), which encodes the template for telomere addition, and therefore operates through a novel mechanism independent of its activity in synthesizing telomere repeats.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Telomere synthesis requires both TERT and TERC.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Expression of TERT mRNA in skin epithelium (data not shown) induced anagen in 5/5 K5-tTA+; tetop-TERT+ mice, whereas all littermate control biopsies were in telogen (6/6, p=0.0009 by Chi square analysis)(Fig. 3h).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Despite the loss of BrdU label, CD34+ cells in the bulge remained in similar numbers, indicating that, under the influence of TERT, stem cells divide but likely self-renew to maintain the CD34+ population.”
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Despite expression of transgenic TERT mRNA in this compartment, proliferation was not substantially altered in the basal layer in i-TERT mice compared to non-transgenic littermates in anagen (4.2 Ki-67+ cells/100μm for i-TERT day 50 compared to 4.3 Ki-67+ cells/100μm for non-transgenic day 28) (Fig. 3e).”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, TERT mRNA was co-expressed with BrdU in LRCs in the bulge region in i-TERT mice (Fig. 3g).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“We found that the promoter element used to direct rtTA expression is strongly active in CD34+ bulge cells in actin-GFP mice24 (Fig. 3f).”
What the sources say
- Not checked yetcites [24] Okabe, M., Ikawa, M., Kominami, K., Nakanishi, T. & Nishimune, Y. ‘Green mice’ as a source of ubiquitous green cells. FEBS Lett. 407, 313–319 (1997) source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, we found no changes in structure, differentiation, or signaling in either hair follicle or interfollicular epidermis in i-TERT mice (Fig. S2, S3).”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 7
- The quote only partly states this claim. 1
- Probably not a substantial claim. 5
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This effect was doxycycline-dependent and occurred with 100% penetrance in i-TERT mice (18/18 in anagen) (chi square analysis, p<0.0001 for i-TERT on vs. off doxycycline, Table S1).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In marked contrast, hair follicles from i-TERT mice on doxycycline were consistently in anagen at day 50 (Fig 1f).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one. The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Telomerase activity strongly correlated with the first and second anagen phases and was not detected during telogen phases (Fig 1b).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Whereas hair follicles from non-transgenic mice remained in telogen during the duration of the time course, follicles from i-TERT mice treated with doxycycline entered anagen by day 9 and were in mid-anagen20 by day 12 (Fig 2b) (chi-square analysis, p=0.005, Table S2).”
What the sources say
- Not checked yetcites [20] Muller-Rover, S. et al. A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J. Invest. Dermatol. 117, 3–15 (2001) source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Northern blot and TRAP assay confirmed doxycycline-dependent induction of the TERT transgene and increased telomerase activity in the skin of i-TERT mice (Fig 1c, d) as well as in other tissues (data not shown).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here we show that conditional activation of TERT protein in mouse skin is sufficient to induce proliferation of hair follicle stem cells and that this function is independent of its role in telomere synthesis.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Telomere synthesis requires both TERT and TERC.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Strikingly, these results show that induction of TERT in telogen follicles is sufficient to initiate a transition to the anagen phase and promote new hair synthesis.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Moreover, recent findings indicate that TERT promotes tumor development even in settings of ample telomere reserve, although the mechanisms underlying these telomere length-independent activities of TERT remain unclear9–13.”
What the sources say
- Not checked yetcites [9] Gonzalez-Suarez, E. et al. Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes. EMBO J. 20, 2619–2630 (2001) source
- Not checked yetcites [10] Artandi, S. E. et al. Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc. Natl Acad. Sci. USA 99, 8191–8196 (2002) source
- Not checked yetcites [11] Stewart, S. A. et al. Telomerase contributes to tumorigenesis by a telomere length-independent mechanism. Proc. Natl Acad. Sci. USA 99, 12606–12611 (2002) source
- Not checked yetcites [12] Chang, S., Khoo, C. M., Naylor, M. L., Maser, R. S. & DePinho, R. A. Telomere-based crisis: functional differences between telomerase activation and ALT in tumour progression. Genes Dev. 17, 88–100 (2003) source
- Not checked yetcites [13] Blasco, M. A. & Hahn, W. C. Evolving views of telomerase and cancer. Trends Cell Biol. 13, 289–294 (2003) source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“While induction of anagen can occur through signals from the dermal papilla30, the lack of detectable levels of TERT mRNA in the dermal papilla (Fig. 1h) makes it unlikely in this case.”
What the sources say
- Not checked yetcites [30] Sato, N., Leopold, P. L. & Crystal, R. G. Induction of the hair growth phase in postnatal mice by localized transient expression of Sonic hedgehog. J. Clin. Invest. 104, 855–864 (1999) source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“consistent with previous observations that BrdU label persists in quiescent bulge cells for more than six months17.”
What the sources say
- Not checked yetcites [17] Braun, K. M. et al. Manipulation of stem cell proliferation and lineage commitment: visualisation of label-retaining cells in wholemounts of mouse epidermis. Development 130, 5241–5255 (2003) source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Initiation of a new anagen cycle depends upon activation of a small number of quiescent stem cells that reside in the bulge, a niche at the follicle base15–19.”
What the sources say
- Not checked yetcites [15] Cotsarelis, G., Sun, T. T. & Lavker, R. M. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61, 1329–1337 (1990) source
- Not checked yetcites [16] Taylor, G., Lehrer, M. S., Jensen, P. J., Sun, T. T. & Lavker, R. M. Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell 102, 451–461 (2000) source
- Not checked yetcites [17] Braun, K. M. et al. Manipulation of stem cell proliferation and lineage commitment: visualisation of label-retaining cells in wholemounts of mouse epidermis. Development 130, 5241–5255 (2003) source
- Not checked yetcites [18] Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004) source
- Not checked yetcites [19] Morris, R. J. et al. Capturing and profiling adult hair follicle stem cells. Nature Biotechnol. 22, 411–417 (2004) source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“In normal tissues, TERT is expressed in stem cells and in progenitor cells3, but its role in these compartments is not fully understood.”
What the sources say
- Not checked yetcites [3] Morrison, S. J., Prowse, K. R., Ho, P. & Weissman, I. L. Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity 5, 207–216 (1996) source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Telomere synthesis requires both TERT and TERC.
“Telomere synthesis requires both TERT and TERC; therefore, if the effects of TERT are retained in a TERC−/− background, telomere extension cannot be required for stem cell activation events mediated by TERT.”
The paper relies on this without support.
The role of TERT in stem cell and progenitor cell compartments is not fully understood.
“In normal tissues, TERT is expressed in stem cells and in progenitor cells3, but its role in these compartments is not fully understood.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“tissues with increased TERT expression also showed increased expression of active β-catenin, as well as of its target gene cyclinD1, which in turn may mediate some of the known effects of TERT improving stem cell mobilization (Flores et al, 2005; Reya & Clevers, 2005; Sarin et al, 2005).”
From Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer (2012) · cites this paper as Sarin et al, 2005
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In particular, we and others have previously demonstrated that TERT over-expression could be acting on the pool of adult stem cells present in tissues, leading to their mobilization and subsequent tissue regeneration (Flores et al, 2005; Sarin et al, 2005).”
From Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer (2012) · cites this paper as Sarin et al, 2005
Experimental — accuracy not yet measuredIn the citing paper
“Interestingly, Tert overexpression can also improve the ability of epidermal stem cells to regenerate the skin and the hair 60, 69 .”
From The common biology of cancer and ageing (2007) · cites this paper as [69]
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Metadata
- Authors
- Sarin, K. Y., Cheung, P., Gilison, D., Lee, E., Tennen, R. I., Wang, E., Artandi, M. K., Oro, A. E., & Artandi, S. E.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Artandi, Steven E.
- Venue
- Nature
- Published
- 2005-08
- Volume
- 436
- Issue
- 7053
- Pages
- 1048-1052
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC1361120
- OpenAlex
- W2085786821
- Semantic Scholar
- a1d495197e4ad7bb2a02c41da2b56eb0a48446e4
- Cited by
- 425
- References
- 30
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 10 · 2023: 10 · 2022: 11 · 2021: 9 · 2020: 17 · 2019: 7 · 2018: 14 · 2017: 13 · 2016: 25 · 2015: 14 · 2014: 17 · 2013: 22 · 2012: 33
- FWCI
- 38.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (R55CA109088, K08CA082176)
- National Institute of General Medical Sciences (T32GM007365)
- Topics
- Health Sciences › Medicine › Dermatology › Hair Growth and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Dentistry › General Dentistry › dental development and anomalies
- Keywords
- telomerase reverse transcriptase, hair follicle stem cells, hair cycle, telogen-to-anagen transition, stem cell proliferation, skin epithelium, telomere maintenance, tissue regeneration, aging
- MeSH terms
- Animals, Bromodeoxyuridine, DNA-Binding Proteins, Enzyme Induction, Mice, Transgenic, RNA, Stem Cells, Hair Follicle, Transgenes, Telomerase, Cell Proliferation, Mice
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