Tag Archives: adipose mesenchymal stem cells

Mechanisms Of Action of NeoGenesis Hair Thickening Serum

Topical application of Hair Thickening Serum (HTS) promotes hair growth by two key means: Providing, 1. Skin and hair follicle endogenous molecules from skin and hair follicle stem cells (Adipose mesenchymal stem cells, fibroblasts, and dermal papillae) that drive and maintain the transition from telogen to anagen, and 2. Botanical ingredients normally derived from healthy diets that support hair growth.

Simple topical application of NeoGenesis Hair Thickening Serum, b.i.d., twice daily.

Let’s look at the hair growth cycle, and some of the many factors affecting hair growth. I’ll then explain some the mechanisms by which HTS drives the hair follicle to the anagen phase.

Figure 1. Schematic of the hair growth cycle and the factors that may influence a transition from anagen to telogen vs. telogen to anagen phase. From Natarelli et al, 2023.

HTS Mechanisms of Action in the Hair Growth Cycle

HTS’ mechanisms of action at the hair follicle are many. Here I consider a simplified summary of some of the pathways that the stem cell released molecules and botanical ingredients activate or inhibit to drive and maintain the follicle’s transition to the anagen phase.

Transition from Anagen to Telogen

Inflammation – An immunoprivileged state in the follicle is needed to drive anagen, and inflammation transitions the follicle to telogen instead (Bertolini et al, 2020). HTS reduces inflammation in the innate and adaptive immune systems by using the secretome from adipose mesenchymal stem cells – both the exosomal fraction and soluble fractions that act synergistically to optimally reduce inflammation (González-Cubero et al, 2022; Mitchell et al, 2019)

Hormone – ADSC secretome inhibits negative effects of DHT on hair growth (Tang et al, 2023; Fu et al, 2025).

Poor Nutrition – HTS contains nutrients to support hair growth. Larix Europaea Wood Extract, containing Dihydroquercetin-glucoside (polyphenol), EGCG (polyphenol catechin), glycine, zinc, Camellia Sinensis Leaf Extract, Santalum Acuminatum Fruit Extract, Citrus Glauca Fruit Extract, Acacia Victoriae Fruit Extract, Trifolium Pratense (Clover) Flower Extract (providing an abundance of polyphenols and antioxidants).

Stress – ADSC secretome mitigates immunological disturbances affecting the hair follicle (HF) and contributing to hair loss. ADSCs are able to suppress lymphocyte proliferation and, inhibit complement activation and dendritic cell differentiation from monocytes and therefore are considered natural immunosuppressants (Salhab et al, 2022).

Transition from Telogen to Anagen

Blood Flow – Secretome of ADSCs promotes angiogenesis and increased blood flow to follicles (Silveira et al, 2022; Zhu et al, 2020)

Direct stimulation of Hair Growth – Exosomes from dermal papillae cells drive hair follicle stem cell proliferation to rebuild hair follicle (Li et al, 2023), while fibroblasts provide many building-block proteins need to reconstruct the follicle architecture as it transitions from telogen to anagen (Suh et al, 2023).

Increased Local Growth factors – Fibroblasts (Lin et al, 2015), ADSCs (Won et al, 2017), and dermal papillae (HU et al, 2020) secretome all provide necessary growth factors to induce transition to anagen

References

Bertolini M et al (2020) Hair follicle immune privilege and its collapse in alopecia areata. Exp Dermatol. 29: 703–725.

Fu Y, Han YT, Xie JL, Liu RQ, Zhao B, Zhang XL, Zhang J, Zhang J. Mesenchymal stem cell exosomes enhance the development of hair follicle to ameliorate androgenetic alopecia. World J Stem Cells 2025; 17(3): 102088

Fu Y, Han YT, Xie JL, Liu RQ, Zhao B, Zhang XL, Zhang J, Zhang J. Mesenchymal stem cell exosomes enhance the development of hair follicle to ameliorate androgenetic alopecia. World J Stem Cells 2025; 17(3): 102088 [PMID: 40160691 DOI: 10.4252/wjsc.v17.i3.102088]

González-Cubero, E et al (2022) María L. González-Fernández, Elias R. Olivera, Vega Villar-Suárez,Extracellular vesicle and soluble fractions of adipose tissue-derived mesenchymal stem cells secretome induce inflammatory cytokines modulation in an in vitro model of discogenic pain,The Spine Journal,Volume 22, Issue 7,2022, Pages 1222-1234

Li J, Zhao B, Yao S, Dai Y, Zhang X, Yang N, Bao Z, Cai J, Chen Y, Wu X. Dermal PapillaCell-Derived Exosomes Regulate Hair Follicle Stem Cell Proliferation via LEF1. Int J Mol Sci. 2023 Feb 16;24(4):3961.

Lin WH, Xiang LJ, Shi HX, Zhang J, Jiang LP, Cai PT, Lin ZL, Lin BB, Huang Y, Zhang HL, Fu XB, Guo DJ, Li XK, Wang XJ, Xiao J. Fibroblast growth factors stimulate hair growth through β-catenin and Shh expression in C57BL/6 mice. Biomed Res Int. 2015;2015:730139.

Mitchell R et al (2019) Secretome of adipose-derived mesenchymal stem cells promotes skeletal muscle regeneration through synergistic action of extracellular vesicle cargo and soluble proteins. Stem Cell Res Ther. 10(1):116.

Natarelli N, Gahoonia N, Sivamani RK (2023) Integrative and Mechanistic Approach to the Hair Growth Cycle and Hair Loss. J Clin Med. 2023 Jan 23;12(3):893.

Salhab O, Khayat L, Alaaeddine N (2022) Stem cell secretome as a mechanism for restoring hair loss due to stress, particularly alopecia areata: narrative review. J Biomed Sci. 2022 Oct 5;29(1):77.

Shiqi Hu et al. (2020) Dermal exosomes containing miR-218-5p promote hair regeneration by regulating β-catenin signaling.Sci. Adv.6,eaba1685(2020).

Silveira BM, Ribeiro TO, Freitas RS, Carreira ACO, Gonçalves MS, Sogayar M, et al. (2022) Secretome from human adipose-derived mesenchymal stem cells promotes blood vessel formation and pericyte coverage in experimental skin repair. PLoS ONE 17(12): e0277863.

Suh SB, Ahn KJ, Kim EJ, Suh JY, Cho SB. (2023) Proteomic Identification and Quantification of Secretory Proteins in Human Dermal Fibroblast-Conditioned Medium for Wound Repair and Hair Regeneration. Clin Cosmet Investig Dermatol. 2023;16:1145-1157

Tang, Xin, Cao, Cuixiang, Liang, Yunxiao, Han, Le, Tu, Bin, Yu, Miao, Wan, Miaojian, Adipose-Derived Stem Cell Exosomes Antagonize the Inhibitory Effect of Dihydrotestosterone on Hair Follicle Growth by Activating Wnt/β-Catenin Pathway, Stem Cells International, 2023, 5548112, 20 pages, 2023.

Won CH et al (2017) The Basic Mechanism of Hair Growth Stimulation by Adipose-derived Stem Cells and Their Secretory Factors. Curr Stem Cell Res Ther. 2017;12(7):535-543

Zhu, D., Johnson, T.K., Wang, Y. et al. (2020) Macrophage M2 polarization induced by exosomes from adipose-derived stem cells contributes to the exosomal proangiogenic effect on mouse ischemic hindlimb. Stem Cell Res Ther 11, 162.

The Skin’s Circadian Rhythm: Skin Permeability Increases at Night

I’m frequently asked if applying skin care products at night is more effective than during the day. Numerous studies provide evidence that if you’re applying a product that is meant to penetrate the skin, it will do so more effectively at night. The Skin’s Circadian Rhythm and Epigenetic Mechanisms are the primary underlying causes. So powerful is the circadian rhythm in humans, that certain cancer drugs working more efficaciously and with greater safety when adminstered at night versus during the day.

When night arrives, and the blue light that suppresses melatonin (a potential epigenetic regulator) is diminished, a remarkable physiological change comes over the body including the skin. Cells, such as fibroblasts in the dermis, have an intrinsic clock, as well as being controlled by systemic influences that is likely, at least partially, under the control of epigenetic mechansisms. Environmental regulators, in this case, blue light, can change the expression (not the sequence structure) of our DNA through epigenetic mechanisms. The mechanisms are the envionmental control of proteins and microRNA that interact with DNA to upregulate or downregulate gene expression, which leads to the making of our proteins and microRNA. In other words, the environmental light is turning-up or -down the expression of proteins and microRNA, which in turn regulates the physiology and anatomy of the skin leading to increased skin permeability at night. Although other studies have found variations at different skin sites, permeability of the skin increases at night for both normal skin and those with atopic dermatitis.

One of the microRNA turned-up at night is microRNA-146a. Fibroblasts are activated to release microRNA-146a during sleep, which will help to activate other cells, dramatically ramp up DNA repair, protein production, and cell division. This activity has evolved to repair the damage caused by the day’s environmental onslaught, such as UV rays and pollution, damage that can lead to chronic inflammation and visible aging.

From: Wahl et al, 2019.

These intricate processes in the skin require complex coordination, a task dependent on the body and the skin’s internal clock mechanism that controls the circadian rhythm. This internal clock system leads to repair in the night hours, when UV rays and other damaging influences are absent or minimized. However this system can become dysregulated through aging, stress levels, lack of sleep, and toxins, pathogens, and allergens.

Adipose Mesenchymal Stem Cell and Fibroblast Secretome – Epigenetic Regulators

Epigenetic regulation is complex. It occurs throughout the body, including the skin. Proteins, such as SIRT1, and micoRNA, such as miR-146a, are two of the many known epigenetic regulators in the skin. Evidence (Heo and Kim, 2022) suggests that human adipose mesenchymal stem cells secrete microRNA 146a (miR-146a). This is also true of human dermal fibroblasts (Stafa et al, 2024), both of which are a part of the NeoGenesis S2RM technology used in our products, such as Recovery, Skin Serum, and Booster. In the human body, miR-146a has many functions, including control of the adaptive immune system by regulating antibody production. Adipose mesenchymal stem cells also control SIRT1 pathways. Loss of SIRT1 function in the skin has many effects, including disruption of barrier function in the epidermis. Skin sensitization and inflammation result. Envornmental regulators, such as particulate matter in the air, induce senescence of skin keratinocytes through oxidative stress-dependent epigenetic modifications. In other words, pollution is inducing aging in keratinocytes through epigenetic changes. Likewise, photaging also has an important epigentic component creating damage. Let’s look at another function of miR-146a that is critical to skin health and involves circadian rhythms in the skin.

Inhibition of miR-146a suppresses activity in one of the cellular clock genes, PER1, and can lead to an increase in cellular damage as well as other changes seen during ageing, such as reduced collagen production and increased inflammation. That’s a double whammy to our collagen. Much of the collagen in the body, including skin, is long-lived with a half-life of 15-30 years. That means some collagen will be with you through most, if not all, of your life. And it accumulates damage from inflammation. Other collagens do turnover more rapidly. Therefore, without miR-146a increasing collagen production and reducing inflammation, the double whammy on collagen is in effect – no new collagen to replace the old, and increasing inflammation to continuously attack the old.

The bottom line here is that you need to sleep (make sure at night to turn-off your TV and its damaging blue light) to induce the proper circadian rhythm, thus enhancing skin reapair. Further, application of skin penetrating topical products will benefit from their application before bedtime.

Why Use Skin-Derived Adipose Mesenchymal Stem Cell Released Molecules in Skincare – A Teleological Explanation

Adipose mesenchymal stem cells (ADSCs) have evolved to arise in the skin during the third trimester of fetal development. These cells arise just before birth so that they can be present following birth to tampen inflammation that may arise in the baby’s new hostile, non-sterile environment where the skin is under constant insult from injuries, toxins, UV, antigens, and pathogens. It’s why ADSCs and the molecules they release are preferred over, 1. bone marrow mesenchymal stem cells and platelets, which serve to induce inflammation and rapid fibrotic scarring, and 2. over umbilical cord mesenchymal stem cells, that have evolved to operate in the sterile conditions of the womb to form the cord, which is unlike skin structure and function, and since it’s a sterile environment, not dampen inflammation which is unneeded and doesn’t happen in the sterile environment where infection can’t happen. The molecules released from ADSCs are the safest and most effective stem cell released molecules to use as skin therapeutics.

Scientist think teleologically often. It’s one of the ways we reason through the discovery and invention of phenomenon. Teleology is relating to or involving the explanation of phenomena in terms of the purpose they serve rather than of the cause by which they arise. In other words, teleology or finality is a branch of causality giving the reason or an explanation for something as a function of its end, its purpose, or its goal, as opposed to as a function of its cause. Why is this thing present, what is it doing?

Adipose mesenchymal stem cells (ADSCs) have evolved to arise in the skin during the third trimester of fetal development and to be present throughout adult life. These cells arise just before birth. So the teleological questions are, why do they arise just before birth, and what are the doing in the adult skin during a person’s lifetime?

Teleologically thinking, the ADSCs are present following birth to tampen inflammation that may arise in the baby’s new hostile, non-sterile environment that presents after birth. The ADSCs arise as tissue specific stem cells in the skin that has developed during the third trimester. The stem cell niche of the skin will help to direct these ADSCs to develop in a manner that is tissue specific and serves to resolve inflammation in that adult skin. This sort of tissue specific development of the ADSCs doesn’t happen in the bone marrow or the umbilical cord, for example. Following birth, the skin is under constant insult from traumatic injuries, toxins, antigens, UV, and pathogens. Those are signals for inflammation. When the skin is compromised by these factors, evolution has given the skin an inflammatory response to fight associated infection. Any of these factors can lead to barrier disruption and an eventual infection, and the inflammatory response is the key to fighting infection. But inflammation is damaging. Not only does infection fight invading pathogens, inflammation also damages our own cells and tissues.

So inflammation has to be tampened, otherwise, if it is prolonged, necroinflammation ensues and our tissues become necrotic or otherwise damaged. Without inflammation being reduced, the damaging inflammatory pathways cause more inflammation and scale-up the damage. And what is present in adult skin to resolve inflammation? It’s the adipose mesenchymal stem cells (ADSCs) and the molecules that they release. In this case, the molecules from ADSCs can help the healing process by a number of mechanisms, including angiogenesis and reducing inflammation. The molecules from ADSCs induce an anti-inflammatory pro-regenerative state in the skin. Diabetic ulcers are example, where the necrotic tissue, such as Necrotizing fasciitis, has to be removed to reduce the inflammation. In these conditions, the ADSCs are no longer present at the site of open wound, and inflammation is hard to control. Addition of ADSC secretome facilitates the healing of the diabetic ulcer through a number of mechanisms, including the reduction of inflammation.

ADSCs are preferred over, 1. bone marrow mesenchymal stem cells and platelets, which serve to induce inflammation and rapid fibrotic scarring, and 2. over umbilical cord or placental mesenchymal stem cells, that have evolved to operate in the sterile conditions of the womb to form the cord, which is unlike skin structure and function, and since it’s a sterile environment, not dampen inflammation.

There’s much hype about cytokines from bone marrow mesenchymal stem cells. I’ve previously blogged about how bad these BMSC molecules are for the skin. Let’s quickly consider inflammation and the stem cells used by AnteAge to make their products: Bone Marrow Mesenchymal Stem Cells (BMSCs), and the molecules they release, prolong and enhance inflammation by increasing survival and function of neutrophils (Castella et al, 2011). Under hypoxic conditions, which induces the activation of TRL4, BMSCs secrete pro-inflammatory factors and decrease the polarization of macrophages from the M1 to M2 phenotype (Faulknor et al, 2017; Waterman et al, 2010). Therefore, BMSCs cultured in normal hypoxic conditions in the laboratory are secreting pro-inflammatory factors and when administered to wounded skin will induce inflammation by recruiting neutrophils and M1 type pro-inflammatory macrophages. When you put AnteAge on your skin, these are the pro-inflammatory molecules damaging your skin.

Safety and efficacy considerations: ADSCs preferred Over BMSCs

I’m asked frequently about the safety of using the molecules from ADSCs, so I’ll address it here. When addressing safety and efficacy concerns of stem cells, we must consider tissue-specific stem cells, first described by Dr. Elly Tanaka, a professor of science at the IMP in Vienna. Choosing the appropriate stem cell type to match the condition to be treated is critical not only to efficacy, but most importantly, safety of the therapeutic. Beyond the genetic and epigenetic factors that influence stem cell phenotype as embryonic stem cells differentiate into somatic stem cells, the immediate niche of the stem cell will have profound influence on the cell’s phenotype. If your wanting to regenerate skin, then use tissue specific stem cells from the skin. ADSCs and their secretome is efficacious and safe. Even ADSCs from cancer patients can been safely used for therapeutic purposes.

We don’t use umbilical cord mesenchymal stem cells (UMSCs) because they are not tissue specific to the skin, and they didn’t evolve to work in adult tissue where inflammation needs to be inhibited. Bone marrow mesenchymal stem cells (BMSCs) do appear in the skin, but only transiently in the skin during open wounds to close the wound quickly (yielding fibrotic scarring). induce inflammation (destructive to tissue), and cause high rates of proliferation (pro-oncogenic). If you think about it, the BMSCs appear transiently during an open wound to fight infection by inducing inflammation, and closing the open wound quickly by hyper-proliferation of cells. BMSCs and their released molecules didn’t evolve to be present in the skin for long periods of time – only transiently. Applying BMSC molecules for an extended time will induce too much inflammation and too much proliferation, leading to long term inflammation, fibrotic scarring, and a pro-oncogenic state.

Beyond their suboptimal efficacy profile, I’ll briefly explain some of the mechanisms underlying our choice of not using BMSCs because of a poor safety profile. The complexity of the bone marrow (BM) niche can lead to many stem cell phenotypes, whether we consider hematopoietic stem cells (HSCs) or bone marrow mesenchymal stem cells (BMSCs). Here I will discuss the properties of BMSCs, not HSCs. Because of the complexity, many BMSC phenotypes exist, including disease causing phenotypes that are varied and hard to distinguish – a part of the problem in using BMSC for therapeutic development. This complication, unlike that for ADSCS, includes recirculated cells, particularly recirculated cancer cells. Once a tumor cell disseminates into the BM, the cancer cell often displays phenotypic characteristics of BMSCs rendering cancer cells difficult to distinguish from BMSCs. BM is a site of BMSCs that may differentiate into HSCs [113] and recirculating blood cells that may differentiate into BMSCs [114,115]. BMSCs are also found outside of the niche in peripheral blood [116] and home into sites of injury [117] and cancer tissue where they are educated into becoming a pro-cancerous phenotype [118]. Recirculated melanoma and myelogenous leukemia cells [119] in BM interact with BMSCs to change the phenotype of the BMSC to one that is cancer promoting by enhancing their proliferation, migration, and invasion and altering the production of proteins involved in the regulation of the cell cycle [120]. Indeed, melanoma tumor cells start to disseminate to BM during the initial steps of tumor development [121]. In breast cancer patients, detection of recirculated cancer cells that disseminated in BM predicts recurrence of the cancer [122]. Cancer cells can fuse with BMSCs and change their phenotype [123], or release exosomes to change the phenotype of BMSCs to cancer promoting [124]. Indeed breast tumor cells fuse spontaneously with bone marrow mesenchymal stem cells [125]. This fusion may facilitate the exchange of cellular material from the cancer cell to the BMSC rendering the fused cell more oncogenic [126]. Further, others have found the same result of this fusion and exchange of cellular material, which has been found to increase metastasis. For example, Feng et al127,found that human hepatocellular carcinoma cells with a low metastatic potential exhibit a significantly increased metastatic potential following fusion with BMSCs in vitro and in xenograft studies. In the end, the BMSCs and their molecules/exosomes, having been conditioned by tumor cells, were found to increase the probability of cancer in human patients [128]. The various phenotypes of BMSCs, including the cancerous phenotypes are difficult to distinguish [36]. In contrast, even ADSCs derived from cancer patients have been found to be safe for therapeutic development [66].

One of many reasons why ADSCs are preferred compared to BMSCs is that ADSCs express a low level of major histocompatibility complex (MHC) class I molecules and do not express MHC class II and costimulatory molecules. Even the exosomes of BMSCs express MHC class II proteins [129]. These problems in BMSCs are amplified when using donor, allogeneic BMSCs that have been replicated many times, essentially aging the cells, during expansion to develop the therapeutic. This is in contradistinction to ADSCs. Critically, when comparing experimental data of BMSCs to ADSCs from the same human donor, “ADSCs have a “younger” phenotype,” according to stem cell scientists [130]. Indeed, Burrow et al found that BMSCs have, among other negative attributes compared to ADSCs, an increased level of senescence compared to matched ADSCs. Senescent cells develop the senescence-associated secretory phenotype (SASP), a pro-inflammatory set of molecules where the local tissue effects of a SASP or specific SASP components have been found to be involved in a wide variety of age-related pathologies in vivo such as hyperplastic diseases, including cancer [131]. Whereas the use of BMSC transplants has a history of medical adverse events, including the induction of cancer in the recipient (Maguire, 2019), fat grafting, along with its constituent ADSCs, have a long history of safety in medical procedures dating back to 1893 when the German surgeon Gustav Neuber transplanted adipose tissue from the arm to the orbit of the eye in an autologous procedure to fill the depressed space resulting from a postinfectious scar [132]. Fat grafting’s long history of being safe, regardless of the harvesting techniques used in patients [120,133], has been recently reviewed by physician-scientists at Baylor College of Medicine [134]. Furthermore, physician-scientists at Stanford University School of Medicine have recently reviewed the safety and efficacy of using ADSCs to augment the outcomes of autologous fat transfers [135]. 136,have found that ADSCs and fat grafting for treating breast cancer-related lymphedema is safe and efficacious during a one year follow-on, where patient-reported outcomes improved significantly with time. In a randomized, comparator-controlled, single-blind, parallel-group, multicenter study in which patients with diabetic foot ulcers were recruited consecutively from four centers, ADSCs in a hydrogel was compared to hydrogel control. Complete wound closure was achieved for 73% in the treatment group and 47% in the control group at week 8. Complete wound closure was achieved for 82% in the treatment group and 53% in the control group at week 12. The Kaplan–Meier (a non-parametric statistic used for small samples or for data without a normal distribution) median times to complete closure were 28.5 and 63.0 days for the treatment group and the control group, respectively [137]. Treatment of patients undergoing radiotherapy with adult ADSCs from lipoaspirate were followed for 31 months and patients with “otherwise untreatable patients exhibiting initial irreversible functional damage” were found to have systematic improvement or remission of symptoms in all of those evaluated [138]. In animal models with a full thickness skin wound, administration of ADSCs, either intravenously, intramuscularly, or topically, accelerates wound healing, with more rapid reepithelialization and increased granulation tissue formation [139], and topically applied the ADSCs improved skin wound healing by reducing inflammation through the induction of macrophage polarization from a pro-inflammatory (M1) to a pro-repair (M2) phenotype [140]. I’ve discussed some of the other mechanism by which ADSCs reduce inflammation in the skin in a recent blog.

Summary

Adipose mesenchymal stem cells (ADSCs), unlike stem cells from tissues other than the skin (BMSCs and UMSCs) and stem cells from non-adult sources in the womb (UMSCs), evolved to work in the skin of adults to inhibit inflammation and to reset the innate and adaptive immune systems of the skin to a anti-inflammatory, pro-regenerative healing state to maintain and regenerate normal, non-fibrotic skin structure and function.

Eczema: Natural Aryl Hydrocarbon Receptor Activation -Another Pathway Through Which Adipose Mesenchymal Stem Cell Secretome Reduces Inflammation

Activation of the aryl hydrocarbon receptor (AhR) through its natural ligands, has been found to reduce skin inflammation, reduce oxidative stress, and upregulate skin barrier protein expression. AhR also inhibits the generation, persistence, and cytokine production of resident memory T cells in the skin. Stem cell released molecules (secretome) from adipose mesenchymal stem cells includes kynurenine, which is an AhR agonist.

The molecules released (secretome) from adipose mesenchymal stem cells (ADSCs) are diverse (Maguire, 2013) and and have many immunotherapeutic actions. Recent studies provide evidence that one mechanism by which the secretome of ADSCs act is through their agonist activities at Aryl hydrocarbon receptors (AhR). Such AhR agonist activity is highly therapeutic to eczema (Eichenfield et al, 2023).

The aryl hydrocarbon receptor (AhR) is expressed in various tissues characterized by a rapid growth rate, including human skin. Kynurenic acid, a product of tryptophan metabolism enzymatically formed from kynurenine, is a natural ligand for AhR. However, AhR is a promiscuous receptor, binding many unnatural ligands such as environmental toxins. This is important, because if the AhR is activated by unnatural ligands, such as air pollution (PM2.5 for example), ill effects can result. The soluble factors (kynurenine and downstream metabolites) generated by IDO (Indoleamine 2,3-dioxygenase) can bind and activate the aryl hydrocarbon receptor to promote Treg cell differentiation and the induction of dendritic cells expressing an immunosuppressive phenotype. Further, in a dose-dependent response, kynurenine upregulates the expression of immunosuppressive genes, such as TGFB1 and IDO1.

Mechanistically, ADSCs release kynurenine, which is a tryptophan metabolite catalyzed by IDO, to activate the aryl hydrocarbon receptor and enhance its downstream target NFE2L2 in macrophages. NFE2L2-encoded NRF2 not only functions as a master regulator of antioxidant defense but also represses the expression of inflammatory genes. As expected, NRF2 upregulation in macrophages was inhibited by inhibiting IDO and 1-methyltryptophan (1-MT), and the anti-inflammatory effect of ADSCs on macrophages was blocked when NRF2 expression in macrophages was silenced. Kynurenic acid, another IDO-derived metabolite that shares the same aryl hydrocarbon receptor as kynurenine, can promote TNF-α-stimulated gene-6 (TSG-6) expression, which is also released from ADSCs, and alleviate neutrophil infiltration of tissues (Wang et al, 2018).

In summary, the secretome from ADSCs contains a number of molecules (IDO, kynurenine, kynurenic acid) that naturally activate aryl hydrocarbon receptors to reduce inflammation in the skin, and provide long term therapeutic benefit to skin diseases such as Eczema and Psoriasis.