Single-keratinocyte transcriptomic analyses identify different clonal types and proliferative potential mediated by FOXM1 in human epidermal stem cells

Enzo, Elena; Seconetti, Alessia Secone; Forcato, Mattia; Tenedini, Elena; Polito, Maria Pia; Sala, Irene; Carulli, Sonia; Contin, Roberta; Peano, Clelia; Tagliafico, Enrico; Bicciato, Silvio; Bondanza, Sergio; Luca, Michele De

doi:10.1038/s41467-021-22779-9

Cited by 44 publications

(59 citation statements)

References 64 publications

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“…Impressive is the change in the morphology of the cells. The keratinocytes onto the “Ma/Col-Ca-polyP-NP” change to a 'cobblestone' pattern, which is characteristic for keratinocytes in the lowermost epidermal cell layer, the stratum basale 33 ; they are the interfollicular epidermis stem cells from where the clonogenic keratinocytes maturate 34 (Figure 3 C and D). In addition and frequently, these cells are covered with numerous microvilli (Figure 3 D).…”

Section: Resultsmentioning

confidence: 99%

Acceleration of chronic wound healing by bio-inorganic polyphosphate: In vitro studies and first clinical applications

Schepler¹,

Neufurth²,

Wang³

et al. 2022

Theranostics

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The healing of chronic wounds is impaired by a lack of metabolic energy. In previous studies, we showed that physiological inorganic polyphosphate (polyP) is a generator of metabolic energy by forming ATP as a result of the enzymatic cleavage of the high-energy phosphoanhydride bonds of this polymer. Therefore, in the present study, we investigated whether the administration of polyP can substitute for the energy deficiency in chronic wound healing. Methods: PolyP was incorporated into collagen mats and applied in vitro and to patients in vivo . Results: (i) In vitro studies: Keratinocytes grown in vitro onto the polyP/collagen mats formed long microvilli to guide them to a favorable environment. HUVEC cells responded to polyP/collagen mats with an increased adhesion and migration propensity as well as penetration into the mats. (ii) In vivo - human clinical studies: In a “bench to bedside” process these promising in vitro results were translated from the laboratory into the clinic. In the proof-of-concept application, the engineered polyP/collagen mats were applied to chronic wounds in patients. Those mats impressively accelerated the re-epithelialization rate, with a reduction of the wound area to 65% after 3 weeks and to 36.6% and 22.5% after 6 and 9 weeks, respectively. Complete healing was achieved and no further treatment was necessary. Biopsy samples from the regenerating wound area showed predominantly myofibroblasts. The wound healing process was supported by the use of a polyP containing moisturizing solution. Conclusion: The results strongly recommend polyP as a beneficial component in mats for a substantial healing of chronic wounds.

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Section: Resultsmentioning

confidence: 99%

Acceleration of chronic wound healing by bio-inorganic polyphosphate: In vitro studies and first clinical applications

Schepler¹,

Neufurth²,

Wang³

et al. 2022

Theranostics

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“…Concerning putative stem cell populations, it seems that spatial location may be more relevant than previously thought, and the authors show the importance of the localization of the different cell populations in relation to epidermal rete ridges. Of note, scRNA-seq analyses of clonogenic keratinocytes in culture showed that the holoclone-forming cells are defined by the expression of FOXM1 gene downstream of YAP [46].…”

Section: Single-cell Analyses Of Keratinocytesmentioning

confidence: 99%

Challenges and Opportunities for the Translation of Single-Cell RNA Sequencing Technologies to Dermatology

Ascensión

Araúzo-Bravo

Izeta

2022

Life

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Skin is a complex and heterogeneous organ at the cellular level. This complexity is beginning to be understood through the application of single-cell genomics and computational tools. A large number of datasets that shed light on how the different human skin cell types interact in homeostasis—and what ceases to work in diverse dermatological diseases—have been generated and are publicly available. However, translation of these novel aspects to the clinic is lacking. This review aims to summarize the state-of-the-art of skin biology using single-cell technologies, with a special focus on skin pathologies and the translation of mechanistic findings to the clinic. The main implications of this review are to summarize the benefits and limitations of single-cell analysis and thus help translate the emerging insights from these novel techniques to the bedside.

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“…Such culture method, first developed by Rheinwald and Green (hereafter R&G) in the mid-1970s, is still regarded as the “gold standard” in clinical settings [ 9 , 10 ]. Notably, R&G conditions do not mimic epidermal homeostasis but rather recapitulate the burst of epidermal regeneration occurring upon wound healing [ 11 ]. Under these conditions, the capacity of individual keratinocyte clones to generate secondary clonogenic cultures can be quantified via morpho-functional clonal analysis.…”

Section: Introductionmentioning

confidence: 99%

“…At the molecular level, holoclones derived from different stratified epithelia, such as the epidermis, the thymic epithelium, and the limbal-corneal epithelium, express elevated levels of the ∆Np63α isoform, a key determinant of keratinocyte cell identity, which is essential for the maintenance of stem cells proliferative potential and survival ability [ 14 , 15 , 16 , 17 ]. A very recent study has further unraveled the transcriptional profiles of human epidermal holoclones at the single-cell level [ 11 ]. Besides possessing elevated p63 levels, holoclone-forming cells selectively express the FOXM1 transcription factor, a YAP target gene required for long-term self-renewal ability.…”

Section: Introductionmentioning

confidence: 99%

“…Colonies with holoclone-like features in vitro and tissue-regenerative ability in vivo have also been isolated by rat whiskers [ 21 ], dog [ 22 ], and murine hair follicle, the latter coinciding with α6 + CD34 + stem cells [ 23 ]. Although murine interfollicular keratinocytes do not give rise to the same clonal categories identified in the corresponding human cultures, human holoclone-forming cells and murine epidermal stem cells directly isolated from murine skin express similar subsets of genes [ 11 , 24 , 25 ], suggesting that holoclones capture a functional status common to stem cells resident of stratified epithelia in several species and contexts.…”

Section: Introductionmentioning

confidence: 99%

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ROCK ‘n TOR: An Outlook on Keratinocyte Stem Cell Expansion in Regenerative Medicine via Protein Kinase Inhibition

Centonze

Ponzone

et al. 2022

Cells

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Keratinocyte stem cells play a fundamental role in homeostasis and repair of stratified epithelial tissues. Transplantation of cultured keratinocytes autografts provides a landmark example of successful cellular therapies by restoring durable integrity in stratified epithelia lost to devastating tissue conditions. Despite the overall success of such procedures, failures still occur in case of paucity of cultured stem cells in therapeutic grafts. Strategies aiming at a further amplification of stem cells during keratinocyte ex vivo expansion may thus extend the applicability of these treatments to subjects in which endogenous stem cells pools are depauperated by aging, trauma, or disease. Pharmacological targeting of stem cell signaling pathways is recently emerging as a powerful strategy for improving stem cell maintenance and/or amplification. Recent experimental data indicate that pharmacological inhibition of two prominent keratinocyte signaling pathways governed by apical mTOR and ROCK protein kinases favor stem cell maintenance and/or amplification ex vivo and may improve the effectiveness of stem cell-based therapeutic procedures. In this review, we highlight the pathophysiological roles of mTOR and ROCK in keratinocyte biology and evaluate existing pre-clinical data on the effects of their inhibition in epithelial stem cell expansion for transplantation purposes.

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Single-keratinocyte transcriptomic analyses identify different clonal types and proliferative potential mediated by FOXM1 in human epidermal stem cells

Cited by 44 publications

References 64 publications

Acceleration of chronic wound healing by bio-inorganic polyphosphate: In vitro studies and first clinical applications

Acceleration of chronic wound healing by bio-inorganic polyphosphate: In vitro studies and first clinical applications

Challenges and Opportunities for the Translation of Single-Cell RNA Sequencing Technologies to Dermatology

ROCK ‘n TOR: An Outlook on Keratinocyte Stem Cell Expansion in Regenerative Medicine via Protein Kinase Inhibition

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