The Tumbar Lab of Tissue Stem Cell Biology

 Cornell University

Projects

I. The organization of epidermal stem/progenitor lineages in adult skin. We have contributed to understanding lineage organization of epithelial stem and progenitor cells in adult skin. Using a method to label cells in vivo based on their proliferation history using an H2B-GFP pulse-chase system, we identified many genes expressed preferentially in the label retaining cells, in both hair follicle and epidermis. Based on these findings, we recently described spatial distribution of two epidermal stem cell populations in two distinct basal regenerative domains. Moreover, we identified similarities of organization between mouse tail scale/inter-scales with human rete ridges/inter-ridges. We began to unravel a possible role of spatial domain organization in epidermal adaptation to UV-response. We identified the first epidermal transit-amplifying cell with maturation-dependent behavior in vivo; we modeled this by adapting and implemented for the first time the mathematical theory known as ‘generalized birth-death model’ to lineage tracing data.

1. Tumbar T, Guasch G, Greco V, Blanpain C, Lowry WE, Rendl M, Fuchs E. (2004). Defining the Ephitelial Stem Cell Niche in Skin. 303(5656), 359-63. PMCID: PMC2405920.

2. Sada A, Jacob F, Leung E, Wang S, White BS, Shalloway D, Tumbar (2016). Defining the Cellular Lineage Hierarchy in Adult Skin Epidermis. Nat Cell Biol. 18(6), 619-31. PMCID: PMC4884151.

3. Ghuwalewala S, Lee SA, Jiang K, Baidya J, Chovatiya G, Kaur P, Shalloway D,Tumbar T. (2022). Binary organization of epidermal basal domains highlights robustness to environmental exposure.  EMBO J. 41(18), e110488. PMCID:    (Available on 2023-08-10).

4. Ghuwalewala S, Jiang K, Ragi S, Shalloway D, Tumbar T. (2022). Transit-amplifying progenitor with maturation-dependent behavior contributes to epidermal renewal. In Press. doi:  10.1101/2022.06.12.495812.

II. Chromatin folding and histone methylation: basic function, regulation, and role in skin biology. Chromatin compaction and nuclear localization is assumed important for transcriptional activation. In our laboratory we ask how chromatin and histone modifying enzymes may control physiological processes in skin biology. Using immunofluorescence, Western blots and 10x Illumina ChIP-seq of sorted hair follicle stem cells we documented global histone H3 trimethylation (K4me3, K27me3, K9me) hypomethylation in quiescent stem cells followed by a reset of high levels during proliferative stages. Using chemical inhibitors, we found that this hypomethylation regulates timely hair cycle progression and wound healing in mouse skin. We currently use mouse genetics to dissect the role of individual histone marks in skin development and in homeostasis.

 1. Lee J, Kang S, Lilja KC, Colletier KJ, Scheitz CJF, Zhang YV, Tumbar T. (2016). Signalling couples hair follicle stem cell quiescence with reduced histone H3 K4/K9/K27me3 for proper tissue homeostasis. Nat Commun. 7, 11278. PMCID:

2. Kang S, Long K, Wang S, Sada A, Tumbar T. (2020). Histone H3 K4/9/27 trimethylation levels affect wound healing and stem cell dynamics in adult skin. Stem Cell Reports. 14(1), 34-48. PMCID: PMC6962642.

III. Hair follicle stem cells: basic characterization and regulation. We used lineage tracing in vivo, tissue kinetics studies, and gene knockout studies to characterize the behavior and regulation of hair follicle stem cells (HFSC) in vivo. We provided the first transcriptional profile of sorted HFSC and demonstrated quantitatively that these cells are extremely quiescent, dividing on average only ~ 30 times in a lifetime. We also demonstrated that HFSCs do not sort out their chromosomes containing the older DNA strands, thus refuting a long-standing model in the field known as the immortal strand hypothesis.   Importantly, our single-cell lineage tracing data supported a population deterministic fate model that did not require asymmetric divisions in worked published in 2009 in Cell Stem Cell; this was followed by a flurry of papers in high profile journals, demonstrating similar mechanisms in the intestine, testis, lung etc.  We found an interesting molecular feedback control in HFSCs that enforces quiescence during homeostasis in the face of critical cyclin dependent kinase inhibitor (p21) loss and uncovered Gata6 as the first HF progenitor (matrix) cell fate regulator in skin.

  1. Waghmare SK, Bansal R, Lee J, Zhang YV, McDermitt DJ, Tumbar (2008). Quantitative Proliferation Dynamics and Random Chromosome Segregation of Hair Follicle Stem Cells. EMBO J. 27(9), 1309-20. PMCID:  PMC2374848.
  2. Zhang YV, Cheong J, Ciapurin N, McDermitt DJ, Tumbar T. (2009). Distinct self-renewal and differentiation phases in the niche of infrequently dividing hair follicle stem cells. Cell Stem Cell. 5(3), 267-78. PMCID:
  3. Wang BA, Zhang VY, Tumbar T. (2017). Gata6 promotes hair follicle matrix progenitor cell renewal by genome maintenance during proliferation. 36(1), 61-78. PMCID: PMC5210152.
  4. Lee J, Hoi CS, Lilja KC, White BS, Lee SE, Shalloway D, Tumbar T. (2013). Runx1 and p21 synergistically limit the extent of hair follicle stem cell quiescence in vivo. Proc Natl Acad Sci U S A. 110(12), 4634-9. PMCID:

IV. Runx1 as a master regulator of hair follicle stem cells (HFSC). We characterized the role and downstream mechanisms of Runx1 – a known master regulator of blood SCs – in the hair follicle. We implicated Runx1 expression in the embryonic dermis in the emergence of adult-type of HFSCs. We showed that Runx1 expression in adult HFSC drives the reversible fate transition between a HFSC and an early progenitor cell, and controls timely HFSC activation and hair cycle progression. Runx1 is absolutely required for drug- and Ras- induced skin and oral tumor initiation and maintenance. Our work was the first to implicate Runx1 in epithelial stem cell regulation promoting epithelial cancers.  We found thousands of target genes downstream of Runx1 implicated in cell cycle control, lipid metabolism, Stat3 and Wnt signaling, and HFSC niche organization.

1. Osorio KM, Lilja KC, Tumbar T. (2011). Runx1 modulates adult hair follicle stem cell emergence and maintenance from distinct embryonic skin compartments. J Cell Biol. 193(1), 235-50. PMCID:

2. Scheitz CJ, Lee TS, McDermitt DJ, Tumbar T. (2012). Defining a tissue stem cell-driven Runx1/Stat3 signalling axis in epithelial cancer. EMBO J. 31(21), 4124-39. PMCID:

3. Lee SE, Sada A, Zhang M, McDermitt DJ, Lu SY, Kemphues KJ, Tumbar T. (2014). Runx1 regulates a reversible transition between hair follicle stem and early progenitor cells in quiescence. Cell Rep. 6(3), 499-513. PMCID:

4. Jain P, Nattakom M, Holowka D, Wang DH, Brenna JT, Tsu Ku A, Nguyen H, Ibrahim SF, Tumbar T. (2018). Runx1 role in epithelial and cancer cell proliferation implicates lipid metabolism and Scd1 and Soat1 activity. Stem Cells. 36(10), 1603-1616. PMCID:

V. Dynamic organization and regulation of VE-cadherin expressing lineages of adult skin. Skin vasculature cross-talking with hair follicle stem cells (HFSCs) is poorly understood. Skin vasculature undergoes dramatic remodeling during adult mouse hair cycle and this is intimately connected with HFSC activation and skin homeostasis during the hair cycle. We suggest a working model in which coordinated remodeling and molecular cross-talking of the adult epithelial and endothelial skin compartments modulate timing of HFSC activation from quiescence for proper tissue homeostasis. Moreover, skin vasculature may control spatial organization of epidermis domains, currently under investigation. In addition, we expand the identity of the VE-cadherin lineage to cell types beyond endothelial cells, identifying a perineurial cell type which ensures skin nerve integrity during normal skin homeostasis.

  1. Li KN, Jain P, He CH, Eun FC, Kang S, Tumbar T. (2019). Skin vasculature and hair follicle cross-talking associated with stem cell activation and tissue homeostasis. 8, e45977. PMCID:  PMC6684267.
  2. Chovatiya G, Ghuwalewala S, Walter LD, Cosgrove BD, Tumbar T. (2021). High-resolution single-cell transcriptomics reveals heterogeneity of self-renewing hair follicle stem cells. Exp Dermatol. 30(4), 457-471. PMCID:
  3. Li KN, Chovatiya G, Ko DY, Sureshbabu S, Tumbar T. Blood endothelial ALK1-BMP4 signaling axis regulates adult hair follicle stem cell activation. EMBO J. 2023 Mar 30:e112196. doi: 10.15252/embj.2022112196. Online ahead of print. PMID: 36994549 [Research Article]
  4. Chovatiya G, Li KN, Li J, Ghuwalewala S, Tumbar T. Alk1 acts in non-endothelial VE-cadherin+ perineurial cells to maintain nerve branching during hair homeostasis. Nat Commun. 2023 Sep 12;14(1):5623. doi: 10.1038/s41467-023-40761-5. [Research Article]