Stem Cells and Acne: What is the connection?
Jan 29, 2016
Acne - What Are You Actually Treating?
The focus of acne has always been the treatment of the following:
- Removal of dead skin Cells
- Kill p.Acnes
- Anti-inflammatories.
- Reduce sebum output
The cause of hyperkeratinisation in acne has often been misunderstood. Originally it was believed to be genetic and that acne sufferers skin had what was termed "retention hyperkeratosis". The focus has been on previously the control of the hyperproliferation of cells. Acne treatment though may be missing a biological event that occurs at the cellular level; the LRIG1 (sebaceous gland progenitor cells) sebaceous stem cells in the isthmus of the sebaceous gland [1]. These cells are the ones that determine if a microcomedone is formed.
Acne stem cell pathways
LRIG1 Stem Cells have 2 pathways: They can differentiate into a sebaceous gland or a comedone. P. acnes in adolescent acne is a trigger for the stem cells differentiating into comedones. P. acnes has mainly been considered as a proinflammatory factor. P.acnes has the ability to initiate comedogenesis and also the formation of microcomedones, even in the absence of no clinical inflammation. The isthmus (the zone where the sebaceous gland duct joins the hair duct) is the zone where the microcomedone develops.
Recent data from lineage tracing of sebaceous stem cells [1], as well as the research on comedogenic xenobiotics [4, 5], has shown that comedone formation is able to be influenced on a tissular level.
The epithelium of the isthmus is the residence for sebaceous gland progenitor cells (LRIG1 cells), the so-called sebaceous gland stem cells. Lineage tracing experiments have shown that the progeny of LRIG1 cells contributes to the epithelium of the isthmus and populates sebaceous glands [7,8]. As you can see from the diagram above these stem cells ONLY reside in the isthmus portion of the sebaceous gland. LRIG cells may therefore differentiate toward either an epithelial type or a sebaceous type and should therefore be primary targets for the treatment of acne. This may also explain the observation that ‘the more comedones, the less mature sebocytes’ in the histology of acne [3, 7].
It is well known that acne clients almost have a "deficiency" in Vitamin A. Retinoic acid has been found to be present in the cells of the isthmus. The stem cells in the isthmus alter the processing of Vitamin A resulting in a Vitamin A deficiency[9].
The activation of the aryl hydrocarbon receptor (AhR) pathway by xenobiotics also alters the differentiation. Tetrachlorodibenzodioxin alters sebogenic differentiation towards epithelial type differentiation with infundibular acanthosis, hyperkeratosis and macrocomedones/MADISH formation [4, 10]. An important observation is that the LRIG1 cells are influenced by xenobiotics. Xenobiotics therefore have been shown to be comedogenic and cause microcomedones to form [2, 12].
What is less known is that there is an endless list of AhR pathway modulators. Food and tobacco smoke are examples. It is known that those who smoke end up with microcomedones as a result [19–23]. These modulators of the AhR pathway might have both negative and positive effects on acne, depending on their distribution and metabolism [13, 14].
The aryl hydrocarbon receptor (AhR) receives much attention for its role in the toxicity of dioxins and dioxin-like PCBs. However, also many other compounds have been reported to bind and activate the AhR, of which natural food components are of special interest. Potatoes, cruciferous vegetables, bread, hamburgers and grapefruit juice contained the most NAhRAs. Food preparation and acid treatment can show a significant effect on the AhR activation.
The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor, which is present in many cell types of mammals, including humans. At the moment, there is still no consensus about the biological function of this receptor. However, it received much attention for its role in the toxicity of dioxins, especially the most potent activator 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [17].
One of the most investigated natural AhR agonists (NAhRAs) is indole-3-carbinol (I3C), which is formed in cruciferous vegetables (Brussels sprouts, broccoli, cabbage) by an enzymatic reaction after crushing of the plant tissues. During consumption, I3C undergoes self-condensation into a number of oligomers and Epidermal CYP2 family cytochromes P450 in the acid environment of the stomach. Although ICZ (indolo[3,2-b]carbazole) is formed in very low amounts (ca 0.0002%), its AhR activating potency is relatively high [18].
What is known is that the activation of AhR agonists induces the expression of the cytochrome P450 1A1 (CYP1A1) gene. The polymorphism of this gene is responsible for acne formation.
Knowing that P.acnes is a factor that contributes to the proginetor cells differentiating into an epithelium cell instead of a sebaceous gland. We can control this process by reducing the amount of sebum production which will reduce the number of bacteria. Antiseptics and antibiotics can also be used to suppress p.Acnes proliferation.
Topical application of Vitamin A corrects the abnormal differentiation in the infundibulum/isthmus epithelium and prevents microcomedones[16,15]. Vitamin A causes an expansion of LRIG1 cells in the sebaceous gland. Topical retinoid use should therefore be revisited as targeting acne-prone normal-looking skin in a preventive dimension, rather than just only as comedolytic.
References:
Jensen KB, Collins CA, Nascimento E, Tan DW, Frye M, Itami S, Watt FM: Lrig1 expression defines a distinct multipotent stem cell population in mammalian epidermis. Cell Stem Cell 2009;4:427–439.
Montagna W: The sebaceous glands; in Montagna W, Ellis RA, Silver AF (eds): Advances in Biology of the Skin. Oxford, Pergamon Press, 1963, pp 167–187.
Plewig G, Kligman AM: Acne and Rosacea. Berlin, Springer, 1993.
Saurat JH, Kaya G, Saxer-Sekulic N, Pardo B, Becker M, Fontao L, Mottu F, Carraux P, Pham X, Barde C, Fontao F, Zennegg M, Schmid P, Schaad O, Descombes P, Sorg O: The cutaneous lesions of dioxin exposure: lessons from the poisoning of V. Yushchenko. Toxicol Sci 2012;125:310–317.
Fontao F, Fontao L, Barnes L, Kaya G, Sorg O, Saurat JH: High susceptibility of LRIG1 sebaceous stem cells to TCDD in mice.
Barnes L, Puenchera J, Saurat JH, Kaya G: Lrig1 and CD44v3 expression in human folliculosebaceous unit. Dermatology 2015; 231: 116–118.
Cunliffe WJ, Holland DB, Jeremy A: Come- done formation: etiology, clinical presentation, and treatment. Clin Dermatol 2004;22: 367–374.
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Everts HB: Endogenous retinoids in the hair follicle and sebaceous gland. Biochim Bio- phys Acta 2012;1821:222–229.
Schäfer M, Willrodt AH, Kurinna S, Link AS, Farwanah H, Geusau A, Gruber F, Sorg O, Huebner AJ, Roop DR, Sandhoff K,Saurat JH, Tschachler E, Schneider MR, Langbein L, Bloch W, Beer HD, Werner S: Activation of Nrf2 in keratinocytes causes chloracne (MADISH)-like skin disease in mice. EMBO Mol Med 2014;6:442–457.
Saurat JH, Sorg O: Chloracne, a misnomer and its implications. Dermatology 2010;221: 23–26.
Contassot E, French LE: New insights into acne pathogenesis: Propionibacterium acnes activates the inflammasome. J Invest Derma- tol 2014;134:310–313.
De Waard WJ, Aarts JM, Peijnenburg AC, De Kok TM, Van Schooten FJ, Hoogenboom LA: Ah receptor agonist activity in frequently consumed food items. Food Addit Contam Part A Chemistry Anal Control Expo Risk Assess 2008;25:779–787.
Connor KT, Harris MA, Edwards MR, Budin- sky RA, Clark GC, Chu AC, Finley BL, Row- lands JC: AH receptor agonist activity in hu- man blood measured with a cell-based bio- assay: evidence for naturally occurring AH receptor ligands in vivo. J Expo Sci Environ Epidemiol 2008;18:369–380.
Rollman O, Vahlquist A: Vitamin A in skin and serum – studies of acne vulgaris, atopic dermatitis, ichthyosis vulgaris and lichen planus. Br J Dermatol 1985;113:405–413.
Skazik C, Amann PM, Heise R, Marquardt Y, Czaja K, Kim A, Ruhl R, Kurschat P, Merk HF, Bickers DR, Baron JM: Downregulation of STRA6 expression in epidermal keratino- cytes leads to hyperproliferation-associated differentiation in both in vitro and in vivo skin models. J Invest Dermatol 2014; 134: 1579–1588.
Hankinson O. 1995. The aryl hydrocarbon receptor complex. Annu Rev Pharmacol Toxicol 35:307-40.
Bjeldanes LF, Kim JY, Grose KR, Bartholomew JC, Bradfield CA. 1991. Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proc Natl Acad Sci U S A 88(21):9543-7.
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