The world of skincare has seen remarkable advancements over the years, with science-driven ingredients revolutionizing how we support skin renewal and repair. Among the most transformative discoveries are growth factors, stem cells, and exosomes each playing a crucial role in skin rejuvenation. But how do they differ, and how has this technology evolved over time? Lets break it down.

Epidermal Growth Factors (EGFs) are naturally occurring proteins that signal skin cells to regenerate, repair damage, and boost collagen and elastin production. In skincare, EGFs help accelerate healing, improve skin texture, and reduce the appearance of fine lines and wrinkles. They are particularly beneficial for aging and compromised skin, promoting a firmer, more youthful complexion.

Historically, the most potent growth factors came from human or animal sources. However, advancements in biotechnology have enabled the creation of lab-synthesized peptides that mimic the exact chemical structure of natural growth factors. These bioengineered peptides have been proven to accelerate skin renewal, smooth fine lines and wrinkles, enhance skin texture, and combat signs of environmental damage.

Stem cells are undifferentiated cells that have the unique ability to develop into various types of specialized cells. In skincare, stem cell extractstypically from plant or human sourcesare used for their rich composition of growth factors, peptides, and antioxidants that support tissue repair.

NeoGenesis, a pioneer in biotech-driven skincare, developed patented SRM technology that enables the harvesting of an array of molecules from multiple adult stem cell types and packages them in a highly bioavailable exosome delivery system. These powerful molecules include growth factors, cytokines, and other signaling proteins that are crucial for the bodys natural healing process. Their regenerative skincare products provide nutrients that mimic and enhance your bodys own natural stem cell function.

While growth factors are signaling proteins, stem cells act as a source of these growth factorsdelivering a broader spectrum of regenerative compounds that can enhance the skins natural repair mechanisms. Unlike single-function growth factors, stem cell released media works holistically to enhance skin resilience, making them ideal for sensitive, damaged, or aging skin. They support wound healing, improve hydration, and strengthen the skin barrier.

Plant-based stem cells provide an excellent source of antioxidants and anti-inflammatory benefits to keep skin protected from oxidative stress to promote renewal. However, they cannot communicate directly with live human stem cells to encourage regeneration.

Exosomes are tiny extracellular vesicles that act as advanced messengers, carrying a concentrated blend of antioxidants, nucleic acids, peptides, and phosphoproteins directly to cells. They transmit messages to a target cell and train that cell to act in a certain way. With this enhanced cell communication, in the skin, exosomes can accelerate repair and optimize collagen production for a more youthful, radiant appearance. Exosomes offer a more stable and potent alternative to traditional growth factors or stem cells, making them one of the most cutting-edge innovations in regenerative skincare.

( plated ) Skin Science is the first and only company to harness the power of platelet-derived exosomes in skincare and is a standout in biotech-driven skincare. Through years of research, they developed their patented Renewosome technology to deliver the power of platelet-derived exosomes in a shelf-stable serum formulated to regenerate the appearance of the skin. Their gentle extraction method preserves the structure, purity, and potency of the exosomes, ensuring stability for 12 months without refrigeration. ( plated ) Skin Sciences revolutionary technology is clinically proven to deliver targeted peptides and powerful antioxidants to support the production of collagen and elastin and improve the appearance of redness, brown spots, dullness, and wrinkles.

Platelets are the most prolific generators of exosomes.

As a first responder to wound sites, platelet-derived exosomes go directly to the area of damage and play a pivotal role in the skins natural regeneration process.

Exosomes deliver precise, self-regulating signals and naturally deactivate once their job is done, eliminating concerns of overproliferation.

Platelets act as the direct messengers of renewing cues rather than functioning as intermediaries, as with other regenerative cells or exosomes.

As compared to stem cell exosomes, it is easier to extract pure, regenerative cells and to control variables for consistency over time.

Exosomes can target multiple skin concerns simultaneously (e.g., aging, inflammation, and pigmentation).

Their ability to provide targeted cell-to-cell communication makes them the most advanced option for promoting long-term skin health.

Late 1990s Growth factors were introduced in topical skincare, derived from human and plant sources.

Mid-late 2000s Stem cells started appearing in skincare products as the potential for skin regeneration was realized and their role in cellular communication and repair was better understood.

2010 to Present Exosomes have emerged as the next generation of regenerative skincare, offering superior results in cellular repair and collagen synthesis.

( plated ) Skin Science Intense Serum: This revolutionary, advanced regenerative treatment utilizes a proprietary blend of platelet-derived exosomes to deliver next-level skin rejuvenation. It is clinically proven to enhance skin renewal and healing by delivering targeted antioxidants and peptides to improve tone, texture, firmness, elasticity, and overall skin health.

NeoGenesis Recovery Serum: This breakthrough healing serum utilizes patented SRM technology to restore skin to a healthy and radiant state, effectively correcting the most damaged skin. It is rich in stem cell-released molecules containing growth factors, antioxidants, proteins, and peptides to promote healing and improve the signs of aging while reducing redness and inflammation.

Rhonda Allison Radiant Renewal Serum: This serum uses powerful peptide epidermal growth factors (EGF) to directly stimulate the proliferation of skin cells, promoting renewal and encouraging a more youthful, revitalized complexion. It also provides strong antioxidant properties while reducing inflammation and brightening uneven pigmentation.

Le Mieux EGF-DNA: Enriched with proprietary epidermal growth factors (EGF), this concentrated serum repairs skin tissue and stimulates the skins own cell renewal properties to promote firmer, healthier, and more radiant skin.

With advancements in growth factors, stem cells, and exosomes, skincare continues to evolve toward more targeted, effective, and biologically intelligent solutions. While growth factors laid the foundation for regenerative skincare, exosomes are now leading the charge, providing unparalleled benefits in skin repair, hydration, and resilience.

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Lets Talk Skin Rejuvenation: Growth Factors, Stem Cells, and Exosomes

Skin Stem Cells Comments Off on Lets Talk Skin Rejuvenation: Growth Factors, Stem Cells, and Exosomes | March 1st, 2025

Skincare can be so confusing these days. With so many emerging ingredients on the market, it's hard to know which ones are right for you to prevent premature aging, repair damage, and keep your skin clear. Lately, we've seen ingredients like growth factors and exosomes have a moment in the spotlight, but there's another potent skin-renewal helper that we often forget about: stem cells.

According to board-certified dermatologist, stem cell scientist, and cosmetic surgeon Nathan Newman, MD, human stem cells aren't always ideal for use in skincare, because they may carry undesirable pathogens and genes, but plant stem cells don't have this issue and communicate almost identically to human ones.

Newman thinks that stem cells trump all the other options out thereand for good reason. I chatted with him about the difference between stem cells, exosomes, and growth factors to get the full picture. Keep reading for everything he had to share.

Newman broke down the difference between the industry's most popular youth-enhancing ingredients right now.

Exosomes: Exosomes are small vesicles that play a role in intercellular communication and tissue regeneration. They can be derived from stem cells, plants, or human cells. "They are usually processed and not used as they are produced by the cells," says Newman. "The products are unstable and need to be processed and preserved. They are not consistent from batch to batch, so each time it is manufactured, it will have a different set of signals."

Growth factors: Similar to exosomes, growth factors are proteins that play a key role in regulation cell growth and survival. They're already produced by various cells in the body, but many companies make synthetic versions to put into skincare formulas. These proteins signal molecules to promote cell proliferation, tissue repair, and the formation of new blood vessels. According to Newman, though, their effects are short-lived and do not always regenerate tissue. Basically, you can think of exosomes as a vehicle to deliver the message and growth factors as the actual message.

Stem cell factors: Plant stem cells, on the other hand, are the means by which cells communicate and impart their actions on other cells in your body. "The entirety of this cellular language is referred to as secretomes," explains Newman. "Some of these factors are released directly into the space in between cells and others need to be packaged, as they will be degraded outside the cell, and delivered from one cell to another cell. This cellular language is a dialogue between cells, and it sets off a domino effect that can influence thousands of cells in your body by what is referred to as paracrine effect (much like hormones do as part of your endocrine effect)."

Plant stem cells use a similar language to communicate as human cells. Plant-derived stem cell factors are also more accepted for use in skincare and don't carry the risks of communicable diseases as human cells do. Honestly, we don't see too many plant stem cellderived products out there on the market, and that's because the process of reproducing the same set of secretosomes from batch to batch is pretty difficult. But Newman has found a way to create an ideal set that helps the skin regenerate.

"For the first time, there is a patented process that allows the stem cells to be grown in such a way that it will not only produce a consistent set of factors, called Consortia Factors, but the process mentors the cells to produce a specific set of directions to direct the skin or hair to regenerate," he says. "In addition, this process allows the use of any cell, human or plant, to be used to produce Consortia Factors. Unlike exosomes, or isolated factors, Consortia Factors utilize a complex, synergistic network of bioactive molecules that mimic the skins natural healing and regenerative environment. This process allows for consistent and reproducible set of signals that can be studied and used for specific purposes, such as wrinkle correction, hair growth, skin tone [correction], etc."

Take a look below at what I'm using from Newman's stem cellrich line.

STEM Natural Intelligence

RePure Foaming Cleanser

This super-gentle cleanser is so easy on the skin and helps protect the skin's microbiome. It's also infused with stem cells that help preserve hydration and boost your skin's glow with antioxidants.

STEM Natural Intelligence

Stem Reset Moisturizing Facial Spray

This little spray is so handy for a refresh throughout the day, and it's so hydrating. It's another great tool to have in your toolbox for barrier repair because it contains moisturizing polysaccharides and antioxidant-rich gooseberry extract. It gives you a quick boost of serious moisture or is great to use as a setting spray.

STEM Natural Intelligence

Regenerative Serum

This is the crme de la crme of stem cellderived skincare. This serum contains the most stem cell factors out of the entire line and is designed to visibly reduce the appearance of wrinkles, promote even skin tone, and boost elasticity. It also help to support the production of collagen in the skin and floods it with antioxidants that give you a boost of radiance.

STEM Natural Intelligence

Stem Renew Day Cream

Containing a host of skin-perfecting ingredients, this day cream is lightweight and noncomedogenic yet still super hydrating. As with all of Stem's products, this cream contains a host of plant-based stem cells along with vitamin E, Coenzyme Q10, and gluconolactone to mildly exfoliate the skin.

STEM Natural Intelligence

Stem Revitalize Night Cream

The night cream is similar but contains niacinamide and bakuchiol extract to help with dark spots and increase cellular turnover. It also supports your body's anti-inflammatory response and is rich in vitamins A, C, D, E, and K.

The Stem Company

ReGlow Complexion

This was an immediate favorite from the brand after I received a facial with it at Newman's office. Like the name suggests, it gives you an immediate glow. My only complaint is that the bottle is super small and goes fast when you use it as often as I do.

Stem Natural Intelligence

ReLeaf Serum

This one is great for calming acne and inflammation because it contains adaptogens like ashwagandha along with antioxidants. It can also be used almost like a comforting balm to soothe aches and pains.

Lilfox

Flower Goo Botanic Ferment Stem Cell Serum

CLEARSTEM Skincare

Cellrenew Collagen Stem Cell Serum

Angela Caglia

Cell Fort Serum

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Everything to Know About Stem Cells From a Dermatologist | Who What Wear

Skin Stem Cells Comments Off on Everything to Know About Stem Cells From a Dermatologist | Who What Wear | March 1st, 2025

Edible Beautys Super Stem Cell Concentrate: The breakthrough skincare innovation thats revolutionising anti-ageing  7NEWS

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Edible Beautys Super Stem Cell Concentrate: The breakthrough skincare innovation thats revolutionising anti-ageing - 7NEWS

Skin Stem Cells Comments Off on Edible Beautys Super Stem Cell Concentrate: The breakthrough skincare innovation thats revolutionising anti-ageing – 7NEWS | March 1st, 2025

Abstract

Exosomes are tiny extracellular vesicles secreted by most cell types, which are filled with proteins, lipids, and nucleic acids (non-coding RNAs, mRNA, DNA), can be released by donor cells to subsequently modulate the function of recipient cells. Skin photoaging is the premature aging of the skin structures over time due to repeated exposure to ultraviolet (UV)which is evidenced by dyspigmentation, telangiectasias, roughness, rhytides, elastosis, and precancerous changes. Exosomes are associated with aging-related processes including, oxidative stress, inflammation, and senescence. Anti-aging features of exosomes have been implicated in various in vitro and pre-clinical studies. Stem cell-derived exosomes can restore skin physiological function and regenerate or rejuvenate damaged skin tissue through various mechanisms such as decreased expression of matrix metalloproteinase (MMP), increased collagen and elastin production, and modulation of intracellular signaling pathways as well as, intercellular communication. All these evidences are promising for the therapeutic potential of exosomes in skin photoaging. This review aims to investigate the molecular mechanisms and the effects of exosomes in photoaging.

Keywords: Skin photoaging, UV-induced signaling, Stem cell, Exosome

The harmful effects of ultraviolet (UV) irradiation on the skin, the largest organ in the body, have resulted in an increased demand for sun-damaged skin care products. Photoaging is the premature aging of human skin due to continuousexposure to UV radiationleads to significant alterations including, irregular pigmentation, telangiectasias, roughness, deep wrinkles, dryness, rhytides, elastosis, and precancerous lesions. Moreover, photoaged skin is associated with cellular and extracellular changes. These changes include high epidermal thickness, disorganization of collagen fibers, accumulation of dystrophic elastic fibers, cell genomic instability, as well as diminished viability, and morphological changes of keratinocytes and human dermal fibroblasts, all of which contribute to the pathogenesis of skin photodamage [1, 2].

Exosomes are nano-sized vesicles that serve as a subgroup of vesiclesinvolved in cell-to-cell communication, containing bioactive ingredients such as lipids, proteins, and nucleic acids for cell-to-cell communications. Exosomes can be easily endocytosed and transfer their contents to recipient cells. Exosome therapy as a cell-free therapeutic intervention is correlated with lower risks of tumorigenicity and immunogenicity, reduced potential for uncontrolled cell differentiation and cell proliferation compared to stem cell therapy. Exosomes also show promise as vehiclesfor drug or gene delivery [3]. A large number of studies have demonstrated the therapeutic implications of stem cell-derived exosomes (including those derived from bone marrow mesenchymal stem cells, umbilical cord-derived mesenchymal stem cells, adipose-derived stem cells, and pluripotent stem cells) in age-related diseases, tissue regeneration, wound healing, and dermatological conditions [4]. The biological functions of exosomes have mostly been investigated in preclinical studies. For example, exosomal mmu-miR-291a-3p could exert anti- senescence effect in human dermal fibroblasts, through TGF- receptor 2 signaling pathway and promote skin wound healing in aged mice [5]. Human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs)-derived exosomes which contain a high concentration of growth factors such as epithelial growth factor (EGF), have been found toincrease collagen production and migration ability of normal fibroblasts. These stem cells-derived exosomes penetrate into the epidermis of skin samples in a time-dependent manner and increase collagen I and elastin while decreasing MMP1 expression [6]. Because of the similarity between the molecular mechanism of aging and photoaging, these findings hold promise for the potential use of exosomes in anti-photoaging-related cosmetics or therapeutics for skin rejuvenation and regeneration.. The cosmetic and therapeutic benefits of exosomes for skin care are mediated through their immunomodulatory function, reduction of oxidative stress, decreasing senescence, and stimulation of extracellular matrix (ECM) components production. The aim of this review is to provide an overview of the molecular mechanism of UV-induced skin aging and to highlight the efficiency of exosomes in skin photoaging.

Photoaging is one of the most common skin defects. In the recent years, many studies have been conducted to understand the underlying mechanisms of skin aging. It has been discovered that a multitude of signaling pathways and molecules are involved in regulating this process [7]. In the subsequent section, we will provide an overview of the current understanding of the mechanisms involved in photoaging.

Many inflammatory pathways activated in response to UV radiation contribute to the generation of reactive oxygen species (ROS) and the degradation of collagen and elastin, which are two proteins responsible for skin elasticity and firmness. Interleukin-1 alpha (IL-1) and interleukin-1 beta (IL-1) are proinflammatory cytokines that are suggested to play a role in the photoaging process. In response to UV radiation, these cytokines are produced and contribute to the inflammation and damage caused by ROS. IL-1 and IL-1 can facilitate the breakdown of collagen and elastin by upregulating the expression of matrix metalloproteinases (MMPs), enzymes responsible for the degradation of these proteins [8]. Similarly,cytokine, like IL-6, can contribute to the breakdown of collagen and elastin by increasing the expression of MMPs. Additionally, IL-6 can promote the formation of senescent cells, which are damaged cells that have stopped dividing and can contribute to the aging process [9]. In addition, Toll-like receptors (TLRs), a type of receptor found in the body's immune system [10] are triggered by UV radiation, resulting in a cascade of inflammatory responses in the skin and finally leading to signs of aging [8]. TLR4 signaling pathway may contribute to the increased amount of IL-6 and IL-8 in the senescent skin cells following UV exposure [11]. UV radiation can induce expression of COX-2, which can lead to inflammation and skin damage in the context of photoaging. UV light-induced MAPK pathway can eventually promote COX-2 production [12, 13]. Other pro-inflammatory cytokines, such as TNF- and IL-1, can also enhance COX-2 synthesis [14]. Moreover, a recent study argued suppression of COX-2 can decrease the UV-induced consequences, underscoring the importance of this protein in photoaging [15].

UV radiation causes the production of ROS in skin cells, leading tooxidative stress. This stress causes damage tocellular components such as lipids, proteins, and DNA, which can lead to cellular dysfunction and ultimately contribute to the signs of photoaging, such as wrinkles, age spots, and loss of skin elasticity. The Nrf2/ARE pathway is a key regulator of the cellular response to oxidative stress, and it plays an important role in protecting skin cells from the damaging effects of UV radiation in photoaging. Under normal conditions, NF-E2-related factor-2 (Nrf2) is sequestered in the cytoplasm by its inhibitor protein, Keap1. However, in response to oxidative stress, Nrf2 dissociates from Keap1 and translocates to the nucleus, where it binds to the antioxidant response element (ARE) in the promoter region of genes that encode antioxidant and detoxification enzymes [1618]. This leads to the activation of these genes and the subsequent synthesis of antioxidant and detoxification enzymes, that help neutralize ROS and prevent oxidative damage [19]. It was shown that upregulation of antioxidant enzymes' expression levels in human skin fibroblasts (HSF) via modulation of the KEAP1-Nrf2/ARE signaling pathway enhances cell antioxidant capacity and reduces UVA-induced ROS and lipid oxidation product malondialdehyde (MDA) [20]. Peroxisomes and peroxisomal enzymes also play a crucial role in regulating the levels of ROS. Investigators indicated the efficiency of catalase and superoxide dismutase in photoaging progression collapses significantly [21].

UV can cause various types of DNA damage, including the formation of pyrimidine dimers (such as thymine dimers), which distort the DNA structure and interfere with normal replication and transcription processes. Moreover, it can lead to the generation of reactive oxygen species and indirectly cause nuclear DNA damage. Base-excision repair is responsible for repairing this type of damage, while UVB radiation directly damages DNA and is repaired through nucleotide excision repair [22]. As individuals age, the efficiency of various DNA repair mechanisms, including NER, BER, double-strand break repair, and mismatch repair, declines [23]. This results in a gradual accumulation of DNA damage over time, particularly in intrinsic aging, which can give rise to aging-related traits. UV exposure can exacerbate this process by causing more DNA damage. Concerning photoaging, prolonged exposure to UV radiation can lead to the accumulation of photoproducts in the skin, surpassing its DNA repair capacity [24]. Moreover, evidence suggeststhat UV-induced telomere mutations, shortening, and telomerase dysfunction might facilitate photoaging and cell death progression [23, 25].

In photoaging, the accumulation of DNA damage can trigger the persistent activation of the p53 pathway, which can contribute to the loss of skin elasticity and the development of wrinkles. Additionally, the ATM/ATR pathway is involved in the response to DNA damage. It activates DNA repair mechanisms and can induce cell cycle arrest to facilitate DNA repair. These pathways can also induce apoptosis if the damage is too severe or if the repair mechanisms are overwhelmed [26, 27]. Poly(ADP-ribose) polymerase-1 (PARP-1) is a well-studied nuclear enzyme that belongs to the PARP superfamily. PARP-1 functions as a sensor for DNA damage.. Upon detecting DNA damage, PARP-1 utilizes NAD+as a substrate to add mono-ADP-ribose or poly(ADP-ribose) (PAR) to various acceptor proteins, including PARP-1 itself. Subsequently, activated PARP-1 can induce DNA repair through a base excision repair [28, 29]. However, high UV exposure can also lead to excessive activation of PARP-1 and therefore lead to depletion of the cellular stores of NAD+and ATP, which can contribute to cell death [30].

One of the important mechanisms implicated in thephotoaging of the skin tissue is programmed cell death or apoptosis. It has been shown that there are a vast number of mechanisms underlying this process during photoaging, and many of them still remain unclear. The cascade begins with the dysregulation of crucial apoptosis-related proteins, including Bax, Bcl-xL, PARP, and caspases. [31]. One study discovered that induced deregulation in apoptotic genes, such as p53, caspase-8 and 3, Bax, and Bcl-2 can interestingly enhance anti-photoaging effects by preventing UVB-induced apoptosis [32]. Furthermore, UV might induce upregulation of MAPK pathway-related genes in the chemokine signaling pathwayresulting in oxidative stress and necrotic cell death [33]. On the other hand, it is shown that UV exposure can directly and indirectly (via induced ROS production) activate the mechanism of neutrophil extracellular traps (NET or netosis) which is an immune programmed cell death pathway in that neutrophils release their DNA and sacrifice themselves. Therefore, UV-induced netosis is suggested as a novel pathway that contributes to photoaging progression [34].

Extracellular matrix (ECM) degradation is one of the main hallmarks of photoaging. Exposure to UV radiation can cause damage to the ECM by inducing the production of MMPs, which are enzymes responsible for breaking down collagen and elastin [35]. The stimulation of the MAPK pathway is the primary regulator of UVR-induced MMP upregulation. In addition, ROS generation is essential for UVR-induced MAPK-mediated signal transduction [36]. The UV-dependent MAPK induction results in MMP-1 overexpression followed by type I collagen (COL-1) degradation [37]. Moreover, another study suggested that inhibition of ERK and p38 protects against UVB-induced photoaging by promoting COL-1 accumulation [38].

In the skin, TGF signaling inhibits keratinocyte development and acts as a profibrotic agent in the dermis. In photoaging, chronic UV exposure triggers the TGF1/SMAD3 signaling pathway and leads to metalloproteinase-induced collagen breakdown and photo inflammation. UV irradiation also induces gene alterations in TGF pathway components such as TGFRI, TGFRII, SMAD2, and SMAD4 [39]. Furthermore, several studies support the idea that increased pro-collagen production through TGF-/Smad pathways, and the expression suppression of MMPs by blocking MAPKs, AP-1, and NF-B pathways could exhibit anti-photoaging effects [4043].

Autophagy is a cellular process that involves the degradation and recycling of damaged or dysfunctional cellular components [44]. In the context of photoaging, studies showed that UV exposure can both induce and inhibit autophagy in a context-dependent manner.. Autophagy plays a complex role, with both protective and harmful effects [45, 46]. On one hand, autophagy can help to remove damaged proteins and organelles and can promote cell survival in response to oxidative stress and DNA damage caused by UV radiation. Autophagy can also help to maintain cellular energy homeostasis, which can be disrupted in response to UV radiation [47]. Specifically, exposure to UVB radiation leads to the direct and rapid activation of three proteins including AMPK, UVRAG, and p53, which in turn activate autophagy [45, 48, 49].

Autophagy can be inhibited by UV radiation and subsequent pro-inflammatory signals such as TNF-, IL-1, and IL-6 [50]. This inhibition of autophagy can contribute to the accumulation of damaged proteins and organelles, leading tocellular dysfunction and development of photoaging [51].

Chronic exposure to UVA irradiation decreases the expression of Bach2 (BTB and CNC homology 1, basic leucine zipper transcription factor 2) in skin fibroblasts,which increasesthe expression of cell senescence-related genes and enhances UVA-induced photoaging. Conversely, overexpression of Bach2 can decrease the expression of cell senescence-related genes. Bach2 plays a critical role in suppressing UVA-induced cell senescence via autophagy by modulating the expression of autophagy-related genes and directly interacting with autophagy-related proteins. The precise molecular mechanism underlying the connection between Bach2 and autophagy remains unknown, and further studies are necessary to elucidate this signaling pathway [52]. Also, another more recent study revealed that autophagy inhibition can result in higher photodamage in fibroblasts. It was shown that colony-stimulating factor 2(CSF2) can enhance autophagy while decreasing the expression level of MMP-1 and MMP-3. The negative correlation between autophagy and mentioned MMPs supports the importance of autophagy in anti-photoaging response. Moreover, the expression of AKT can influence the activation of autophagy, which is overexpressed along with the JAK2/STAT3 pathway and may contribute to several severe UV-induced consequences [46]. Collectively, the impact of autophagy during photoaging depends on its balance with apoptosis induction, while more studies are needed to investigate the impact of autophagy in photoaging.

Heat shock protein 27 (HSP27), a member of heat shock protein family, has been implicated in various cellular processes, including stress response, apoptosis, and cytoskeletal organization [53]. HSP27 has been shown to interact with several proteins involved in the regulation of oxidative stress, apoptosis, and aging, such as Bcl-2, p53, p21, and p16 after UV exposure [54]. Reduction in HSP27 expression has been associated with increased levels of MMP-1 and MMP-3, along with the downregulation of type I collagen [55]. Furthermore, the suppression of HSP27 expression can partially enhance apoptosis through further activation of p65 and caspase-3 [56]. These interactions can modulate the balance between cell survival and death, ECM degradation, and oxidative stress response in response to UV radiation.

Skin-associated adipose tissue, consisting of dermal (DWAT) and subcutaneous (SWAT) adipocytes, is critical in skin photoaging. In particular, DWAT, located in the reticular dermis of the skin, serves as a unique layer of adipocytes that can extend into the upper dermis and create a "fat bridge" between the skin surface and subcutaneous fat, linking the area directly exposed to UV radiation with the deeper fat layer [57, 58]. However, the turnover rate of DWAT adipocytes exceeds that of SWAT, and long-term excessive exposure to UV radiation can lead to DWAT depletion and skin fibrosis due to adipocyte-myofibroblast transition [59, 60]. This transition results in the replacement of fibrosis with DWAT volume, causing an uneven skin structure and the formation of skin folds [61]. UV radiation induces the activation of the TGF- signaling pathway, which contributes to the conversion of adipocytes to myofibroblasts, resulting in the depletion of DWAT [62].

In addition to DWAT, SWAT also plays a crucial role in skin photoaging [63, 64]. Proinflammatory chemokines (IL-6 and IL-8) deregulation and their regulatory pathways (JAK pathway) due to UV-induction can lead to SWAT depletion and thinning of connective tissue, resulting in skin atrophy and wrinkle formation [65]. Moreover, chronic UV radiation inhibits the differentiation of preadipocytes and reduces the accumulation of triglycerides in mature adipocytes due to the decrease in lipid synthesis, including acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD), sterol regulatory element binding proteins (SREBPs), and peroxisome proliferator-activated receptors (PPAR) expression [66]. The decrease in both DWAT and SWAT contributes to the overall deterioration of skin structure and function in photoaging.

Exosomes are a subclass of extracellular vesicles with a size less than<150nm in diameter that facilitates intercellular communication [67]. Exosome biogenesis begins with formation of early endosomes through the invagination of plasma membrane which later generates multivesicular bodies (MVBs) containing Intraluminal Vesicles (ILV) (Fig.1). During maturation of early endosomes to late endosomes or MVBs, the cargoes are incorporated into ILVs. ILVs are formed through the (endosomal sorting complex required for transport) ESCRT-regulated mechanism. The ESCRT is a family of proteins consist of ESCRT-0, -I, -II, -III, and Vps4which are essential for vesicle budding, cargo sorting, and the formation of ILVs [68]. Recent evidence showed there is a second mechanism for exosome formationand cargo sorting in an ESCRT-independent manner which involves proteins such as tetraspanin [69]. The MVBs can fuse with the plasma membrane to release ILVs, which are called exosomes, to the extracellular environment. Exosomes include various proteins that participate in the formation and secretion of vesicles (Rab GTPase), proteins, major histocompatibility complex (MHC) proteins (MHC I and MHC II), tetraspanin family, heat shock proteins, and cytoskeleton proteins. Exosomes may carry other cell-specific proteins which their presence depends on pathophysiological conditions [68, 70].

Exosome are small membrane vesicles that are formed by internalization of plasma membrane and formation of early endosomes. The early endosomes transform to late endosomes through maturation, then late endosomes, which termed as multivesicular bodies (MVBs), undergo inward membrane budding intraluminal vesicles (ILVs). MVBs fusion with the plasma membrane leads to release ILVs, or exosomes, into the extracellular space. Exosomes contain various biomolecules depends on the cell type of origin. Lipids, proteins and nucleic acids are the common molecular constituents of the majority of exosomes [67]. Exosomes are also rich in cytokines, growth factor and antioxidant

The release of exosome is regulated by the SNARE proteins, RABs, and other Ras GTPase proteins. Rab GTPases is the member of Ras superfamily of GTPases and is responsible for the formation, membrane fusion, and secretion of vesicles. There are four Rab GTPase proteins including RAB7, RAB11, RAB27, and RAB35,whichare involved in the formation and release of exosome. SNARE proteins mediate the fusion exosome with the plasma membrane or the membrane of organelles [71]. After fusion with plasma membrane, exosomes are released into the extracellular environment and deliver signals to recipient cells through different mechanisms. They can directly merge with the cell membrane and release their contents, interact with cell surface receptors through exosomal surface proteins, or undergoes endocytic uptake [70].

Cells can release exosomes with different sizes, contents, and functional effects on the target cells. At present, different methods are used to separate distinct subpopulations of exosomes. Among them, ultracentrifugation is the most common method that can separate exosomes based on their size and density. Other methods such as polymer precipitation, size-exclusion chromatography, and immunoaffinity are also used to isolate exosomes [72]. The isolated exosomes are then characterizedby analyzing the exosomal markers. Exosomes contain two types of protein. The first group is the common proteins including tetraspanin family (CD9, CD63, CD81), cytoskeletal proteins (actin, tubulin), heat shock proteins (HSP70, HSP90), and the presence of exosome can be confirmed by identification of these proteins. Other specific proteins are varying depending on the cell of origin, for example exosomes derived from malignant tumors contain tumor antigens, which can be used to determine the origin of exosome, related disease and response to the specific treatment [73]. Besides proteins, exosomes contain lipids, mRNA, and other small RNA such as miRNA and other non-coding RNAs. Exosomes have the ability to transfer their genetic contents into the recipient cells and modify different cellular functions. Moreover, they have the potential to be used as diagnostic biomarkers or therapeutic tools for different pathologies [67].

Some studies have indicated that different cells including stem cells and non-stem cells can release exosomes and exert therapeutic effect against photoaging (Table1), which will be discussed in the next sections.

In vitro and in vivo studies have proved the therapeutic potential of exosomes in amelioration ofskinphotoaging

HSF cells, Kunming mice

UVB-irradiated mice

Human umbilical cord mesenchymal stem cells (HucMSCs) are mesenchymal stem cells that are collected from the different parts of the human umbilical cord. These cells possess the ability to self-renew and differentiate into multiple cell types, including osteoblasts, chondrocytes, and adipocytes. HucMSCs exhibit immunomodulatory, anti-inflammatory, and anti-oxidative properties, making them promising candidates for cell therapy and regenerative medicine [83].

Recent studies have investigated the effects of HucMSC-derived exosomes on mitigating the harmful consequences of UV exposure on the skin. Specifically, researchers focused on the role of 143-3, a protein found in HucMSC exosomes, and its interaction with SIRT1. The study demonstrated that HucMSC exosomes containing 143-3 could effectively protect skin cells from UV-induced damage by reducing oxidative stress and inflammation by mediating the SIRT1 pathway [74]. Moreover, these exosomes can enhance the proliferation and migration of HaCaT keratinocytes while inhibiting UVB-induced damage. The findings also show that these exosomes can reduce apoptosis and senescence, increase collagen type I expression, and decrease matrix metalloproteinase (MMP1) expression in photo-aged skin cells [84, 85].

The process of adipocyte development from mesenchymal cells is a multifaceted series of events, both transcriptional and non-transcriptional, that takes place throughout the lifespan of humans. Cells with preadipocyte traits can be derived from adipose tissue in adult individuals and can be grown in vitro. These cells can then be encouraged to differentiate into adipocytes [86].

The role of exosomes derived from adipose tissue-derived stem cells (ADSCs) in preventing photoaging has been extensively studied. Studies indicate that these exosomes effectively inhibit UVB-induced cellular DNA damage through ROS downregulation. Moreover, they can also significantly prevent MMP-1, MMP-3, and COL-3 overexpression and, therefore, protect the ECM integrity. These exosomes may also regulate Nrf2 and MAPK/AP-1 and activate TGF-/Smad pathways upstream of the latter ones [87, 88].

Furthermore, studies have also shown that miR-1246, a highly prevalent nucleic acid in ADSC-derived exosomes, inhibits the MAPK/AP-1 signaling pathway to reduce MMP-1 production and activates the TGF-/Smad pathway, resulting in enhanced pro-collagen type I secretion and an anti-inflammatory impact. In-vivo experiments on Kunming mice demonstrated that miR-1246 might protect against UVB-induced skin photoaging by inhibiting the production of wrinkles, epidermal thickening, and collagen fiber loss. Together, these findings suggest that exosomes derived from ADSCs, particularly miR-1246, play a vital role in the treatment of photoaging by regulating various signaling pathways [75]. Moreover, lncRNA H19, a reach component of ADSC-derived exosomes, shows MMP inhibition and COL-1 production effect on UVB-irradiated mice. It can also sponge miR-138 to target SIRT1, therefore mediating SIRT1 expression and its anti-photoaging impact [76].

Bone marrow mesenchymal stem cells (BM-MSCs) are a type of adult stem cells that have great therapeutic potential in regenerative medicine. Exosomes secreted by BM-MSCs have emerged as a crucial component of their paracrine signaling mechanisms. BM-MSC-derived exosomes contain a variety of bioactive molecules, such as growth factors, cytokines, and miRNAs, that can promote tissue repair and regeneration in various injury and disease models [89].

It is shown that BM-MSCs can mitigate UV-induced oxidative stress and inflammation in a dose-dependent manner and increase cell viability in human dermal fibroblasts (HDFs). BMSCs-exosomes also reduced the expression of MMP-1 and MMP-3 while promoting the expression of COL-1 by reversing MAPK/AP-1 pathway [90]. Moreover, miR-29b-3p, which is found in BM-MSCs-derived exosomes, can participate in reversion of UVB-induced HDF migration suppression, oxidative stress increase, and apoptosis promotion. It is suggested that mentioned miRNA can target MMP-2 and thus prevent COL-1 degradation [77].

Induced pluripotent stem cells (iPSCs) are a type of stem cells that are generated by reprogramming adult cells, such as skin cells, to an embryonic-like state. iPSCs have the ability to differentiate into virtually any cell type in the body and have significant potential for regenerative medicine and drug discovery. iPSCs were first successfully created in 2006 by reprogramming human skin cells using a combination of four transcription factors, including Oct4, Sox2, Klf4, and c-Myc. This discovery was a significant breakthrough in the field of stem cell research and has led to a greater understanding of cellular reprogramming and its potential applications in the future [9193].

It was observed that exosomes derived from human iPSCs (iPSCs-Exo) promoted the proliferation and migration of HDFs under normal conditions. Upon UVB irradiation, HDFs were damaged and overexpressed matrix-degrading enzymes (MMP-1/3), but pretreatment with iPSCs-Exo inhibited these damages. iPSCs-Exo also increased the expression of collagen type I in photo-aged HDFs. Furthermore, iPSCs-Exo significantly reduced the expression of SA--Gal and MMP-1/3 and restored the expression of COL-1 senescent HDFs [78]. SA--Gal is known to be a switch that shifts cells toward senescence fate and is known as an aging marker [94]. Therefore, these results suggest that iPSCs-Exo may have therapeutic potential in the treatment of skin aging.

Human dermal fibroblasts (HDFs) are the main cells in skin derived from MSCs, which play a critical role in extracellular matrix (ECM) remodeling and providing integrity and elasticity to the skin. In the process of skin aging, HDFs proliferation is declined, with decreased collagen production and increased MMPs, resulting in the degradation of the ECM. All of these processes lead to loss of integrity and elasticity and the formation of wrinkles.

Exosomes secreted by human dermal fibroblast cell UVB-irradiated human dermal fibroblasts (UVB-HDFs) are associated with skin photoaging. The analysis of miRNA expression profiling showed the number of dysregulated miRNAs in extracellular vesicles (EVs) derived from UVB-irradiated HDF. Upon UVB-irradiation, expression of miRNA-22-5p was significantly increased in HDF cells and their derived EVs, and can be transferred to other HDFs cells. further analysis showed that miRNA-22-5p upregulation promotes photoaging by targeting growth differentiation factor 11 (GDF11), a protein that protects HDF cells from photoaging [79]. In another study, exosomes derived from three-dimensional (3D) aggregation of HDF cells or spheroid induced collagen synthesis and reduced inflammation in a photoaged skin of mice model. It was hypothesis that miR-133a and miR-223 were upregulated and miR-196a was downregulated in the exosome derived from 3D cultured HDF spheroids, which might inhibit MMP expression, enhance collagen restoring and replacing and activate TGF- signal pathway. Thus 3D HDF-XOs can be used as an effective approach to prevent skin photoaging [80].

Human umbilical vein endothelial cell(HUVEC) is a model cell line to study endothelial cells and can be derived from umbilical cords. Recently, Ellistasari et al. have conducted an in vitro study to investigate the effect of exosomes derived from HUVEC cells in attenuating skin photoaging. They observed that Exo-HUVEC can markedly increase cell proliferation and collagen synthesis in UVB-irradiated fibroblasts, Moreover, Exo-HUVEC can decrease MMP expression which leads to inhibiting collagen degradation in the photoaged cell line model. This source of exosome has the potential efficiency to prevent and treat skin photoaging [81]. Exosome sources are not limited to animal cells. Interestingly, natural exosomes, that originate from plants or other organisms, contain more bioactive molecules than those derived from animal cells. In the study by Han et al. exosome-like nanovesicles derived from a medicinal mushroom, Phellinus linteus (PL), has been shown to have anti-aging and anticancer effects. The fungi exosome-like nanovesicles (FELNVs) can protect skin from UV-induced photoaging. It was shown that fungal EVs are enriched with different miRNAs including miR-CM1-5, and among them miR-CM1 could protect HaCaT cells from UV-induced damage. MiR-CM1 exerts a protective effect through reduction of aging-related markers such as SA--Gal, ROS level, MMP1, and COL1A2 expression. Mical2 was known as a direct target of miR-CM1 which is involved in the regulation of age-related processes [82].

In recent years, exosomes have been exploited as a novel candidate for treatment of many diseases including central nervous system disorders, cardiovascular diseases, and cancer. Under the pathophysiological condition, biological components of exosomes are changed, reflecting the alteration in the cell functions. The alteration in the exosomal components can be served as diagnostic and prognostic biomarkers in many diseases from cancer to aging [95]. Exosomes can be extracted from cell culture, tissues, and biological fluids including plasma, serum, urine, etc. [96]. Exosomes can act locally or transported to distant tissues via body fluids and modulate the function of target cells [97].

Mesenchymal stem cells are multipotent stem cells that that possess a the high ability to release exosome and can be extracted from bone marrow, umbilical cord, and adipose tissue [98]. Exosome therapy as a cell-free strategy offers severaladvantages of small size, no risk of tumorigenicity, and long-term storage making it a potentially safer and more effective alternative to stem cell therapy [3]. Also, exosomes show great promises as the drug delivery carrier due to high stability, biocompatibility, and low immunogenicity compared to virus-based delivery and other non-viral methods. However, there are still some challenges for the application of exosomes in clinics such as low yield of isolation [72].

Preclinical investigations showed that exosomes may have a therapeutic role in aging and other age-related diseases [99]. Cellular aging is due to various biological changes including, epigenetic alteration, genomic instability, senescence, oxidative stress, mitochondrial decline, and dysregulation of intracellular communication [100]. Some studies have demonstrated the therapeutic potential of exosome in preclinical models of age-related diseases such as Alzheimers, Type 2 diabetes (T2DM), osteoarthritis, chronic kidney disease, etc. [99].

Exosomes have many beneficial effects for skin care as they contain various biological molecules that can help to promote skin repair and regeneration [101]. Previous studies have demonstrated that exosomes and other EVs have therapeutic benefits in skin defects such as wound and aging. Most of these studies on the potential use of exosomes in skin repair have been conducted in animal models. For example, it was found that bioengineered exosomes loaded with miRNA-542-3p, derived from bone marrow MSCs (BMMSCs), could promote cell proliferation, collagen synthesis, and wound closure in mice models. Currently, the clinical applicability of exosome-based therapy is limited to skin wound repair [102]. To date, there is no clinical trial has been conducted on exosome in photoaging.

Exosomes are able to deliver various bioactive compounds into the skin cells, which can effectively delay skin aging and inhibit photoaging signatures. These nanovesicles would be artificially engineered with desired biological molecules [4, 103]. Exosomes can be delivered to skin through various invasive and non-invasive methods. In the non-invasive treatment exosomes are incorporated into topical creams, serums, oils, and masks to cover and protect skin [104]. Exosomes can also be incorporated into bioactive polymeric materials like hydrogel, allowing for sustained release, pH maintenance, and enhanced regenerative potential [105]. Local injection is the invasive type of treatment in which anti-aging molecules are injected into the inner layer of skin to enhance therapeutic effects and overcome skin barrier. Subdermal injection of ADSCs has been demonstrated to be effective in reducing anti-photogaing effects through ECM remodeling and neoelastogenesis (Fig.2) [106]. Since MSCs-derived exosomes represent biological activity corresponding to these stem cells, similar and even more effective therapeutic outcome is expected in exosome-based therapeutic protocols. Local injection provides more effective skin treatment compared to topical products due to skipping skin barrier [104]. The stability of exosomes is critical both before and after injection. Exosome lyophilization is often used to increase stability and maintain the activity of biological molecules. This method involves in dehydration and drying of exosome under vacuum condition at low temperature, resulting in their longer storage without loss of activity [107]. Systemic treatment is another method previously used to deliver exosomes through intravenous injection. It has been shown that topical application of exosome combined with intravenous injection effectively accelerates non-diabetic wound healing [108]. Exosomes stimulate collagen production in photoaged skin and reduce the appearance of pigmentation [4]. Moreover,photoaging is associated with a greater risk of malignant tumors like melanoma [109]. Thus, treatment of skin photoaging has important clinical significance and exosome-based therapy could be a helpful method not only in cosmetic application but also in skin cancer prevention.

Exosomes derived from different types of stem cells can play an important role in reducing photoaging by entering the target cells and transferring their contents. UV radiation induce generation of reactive oxygen species (ROS), leading to DNA damage, activation of inflammatory pathway, production of matrix metalloproteinases (MMPs) and degradation of collagen fibers. Skin photoaging is characterized by structural change, appearance of wrinkles and pigmentation (Reviewed in [7]). Exosomes derived from stem cells can be served as novel treatment option for skin repair and regeneration. Administering exosomes in the form of lyophilized injection may be one of the effective approaches to repair photo-damaged skin

Photoaging is a prominent manifestation of skin aging characterized by the appearance of mottled pigmentation, fine lines, and wrinkles. The main molecular mechanisms of photoaging are accumulation of reactive oxygen species, cellular senescence, inflammation, and collagen degradation. Targeting these pathways through novel therapeutics is an intriguing area of study in regenerative medicine. Exosomes are able to regulate multiple cellular processes due to their important role in cellular communication. In the last years, exosomes have emerged as a novel therapeutic option for treatment of many diseases. This review aims to summarize the current findings on the roles of exosomes, particularly those derived from stem cells, in the context of skin photoaging. While most studies investigating the use of exosomes in treating skin defects have been conducted at the preclinical level, additional research is needed to evaluate the therapeutic potentials and clinical values of exosomes in the field of skin treatment medicine.

None.

Reactive oxygen species

Interleukin

Matrix metalloproteinase

Toll-like receptor

Mitogen-activated protein kinase

Cyclooxygenase-2

Tumor necrosis factor-alpha

Nuclear factor kappa B

IB kinase

Inhibitory kappa B

NF-E2-related factor-2

Antioxidant response element

Deacetylase silent information regulator 1

PAR coactivator-1

Human skin fibroblast

Malondialdehyde

Poly(ADP-ribose) polymerase-1

Neutrophil extracellular traps

Extracellular signal-regulated kinase

C-Jun amino-terminal kinase

Collagen

AMP-activated protein kinase

UV radiation resistance-associated gene

Tuberous sclerosis complex

BTB and CNC homology 1, basic leucine zipper transcription factor 2

Broad complex, tramtrack, bric-a-brac/poxvirus, and zinc finger

Heat shock protein

Dermal white adipose tissue

Subcutaneous white adipose tissue

Acetyl-CoA carboxylase

Fatty acid synthase

Stearoyl-CoA desaturase

Sterol regulatory element binding proteins

Peroxisome proliferator-activated receptor

A.HN., N.M. and M.HS. wrote the manuscript. MH.S. conceived the original idea and drafted the manuscript. All listed authors read and approved the final manuscript.

None.

Not applicable.

The authors declare no competing interests.

Publishers Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Not applicable.

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Dr. Inta Gribonika in the lab at NIH

Everyones skin may be tougher than they realize. Research led by Dr. Inta Gribonika, a postdoctoral NIH fellow, demonstrates that skin is more than simply a cover from the outside world; it can offer a first line of defense against infection, paving the way for new kinds of therapies.

Gribonika recently completed a four-year stint as a visiting fellow in the Laboratory of Host Immunity and Microbiome at the National Institute of Allergy and Infectious Diseases (NIAID). During her time at NIH, she contributed new knowledge about the skins role in immune response, research that recently was published in Nature.

Her findings show that the skin can act as a lymphoid organ. In other words, a specific immune response can actually be primed in the skin.

Gribonika is a mucosal immunologist. Her doctoral research had focused on how an immune response could be induced in the gastrointestinal tract after vaccination. After reading that the bacteria living naturally on skin is coated in antibodies, she began to wonder how the body could generate antibodieswhich it normally would do against an infectionaround something thats generally harmless.

Up until now, we were thinking that B cellsthe lymphocytes that produce antibodieswere not living in the skin or coming toward the skin tissue at homeostasis, she said. Her experiments show that B cells do exist in healthy skin.

In the lab, Gribonika painted a beneficial bacterium, S.epidermidis, onto the skin of mice. This bacterium is commonly found on human skin, but not on mice.

I showed that, indeed, skin can recognize this new harmless member of microbiota and generate specific humoral immunity against it, she said. This can happen without any help from professional immune organs, such as the spleen or lymph nodes.

The antibody works as a barrier protection, Gribonika said. It works as a health insurance in case this one new member of commensal microbiota that we now acquired decides at some point in the future to become nasty and infect us.

The ability of harmless bacteria on the skin to stimulate an immune response without inflammation opens a world of possibility for topical medications and vaccines. They could be formulated in a cream that anyone could apply to the skin.

This route is so interesting because its noninvasive and you wouldnt need a clinical practitioner to help you apply the medicine, Gribonika said.

In reflecting on her time at NIH, Gribonika emphasized how much she enjoyed getting to know the people in the lab. Each investigator had his or her own project, but they all supported each other. And they came from all over the world, bringing their different cultures and perspectives, which she found especially enriching.

NIH is probably the best place on Earth to do research, she said. There are so many resources, and the community is so welcoming and willing to share.

When she arrived at NIH, Dr. Yasmine Belkaid was her lab chief. She described Belkaid as a visionary who encouraged her trainees to think big. She gave me the space and freedom to ask the questions I wanted to pursue, Gribonika said.

Gribonika studied biology at the University of Latvia in Riga.

Photo: Sergei25/Shutterstock

Gribonika first became interested in science at a young age. My mom and dad would always read to me about great discoveries and about the people who made them, she recounted. These stories sparked her imagination and got her thinking about nature and the world from different perspectives.

I got interested in science to question whats therewhat we can see and what we cant see, Gribonika said. Immunology is heavily focused on microscopy, on the things we dont see just by looking at our skin. But if you ask the right questions and use the right antibody to target the right thing, all of a sudden you see all these interesting things happening in and on the skin.

Gribonika is a native of Latvia, a small northern European country with less than two million people. As her friend Daina Bolsteins, an administrative assistant at NIAID who is also of Latvian descent, noted, Latvia is better known for producing basketball and hockey players, opera singers and symphony conductors than for producing scientists. Gribonika said she hopes her story will inspire other aspiring scientists from her country.

In March, Gribonika headed to Sweden to begin a new chapter as a tenure-track investigator at Lund University.

Her advice to young investigators? Never give up. Remember why you chose this path in the first place, she said.

If the data disproves your hypothesis, follow the data. If the data conflicts, repeat with other methods and protocols. Be cautious. Verify.

Such rigor in research, she said, opens the door to learning new concepts about the human immune system and overall health.

Results will take you to places you never thought of, she said. Theres a lot of novelty out there.

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Four-year-old donates stem cells to save her baby sister from blood cancer in Odisha  The Hindu

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