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Abstract

Despite extensive research and increased public awareness regarding the adverse health effects of tobacco, the prevalence of cigarette smoking continues to rise, resulting in millions of annual deaths attributed to its use. Consistently, cigarette smoke contains harmful toxins that adversely affect all organs, tissues, and cells. As regenerative medicine is developing with the successful application of mesenchymal stem cells (MSCs) in numerous diseases, it is mandatory to elaborate on the factors that may impair or change the regenerative potential of MSCs. It is well established that cigarette smoke negatively affects the function of MSCs; this impairment has critical implications for regenerative medicine, which emphasizes the need to consider patient smoking history prior to application of MSCs. The review elaborates on primary toxic compounds of cigarette smoke as well as its impact on MSC functions such as proliferation and viability, migratory potential, differentiation, and finally immunomodulation, suggesting avenues for further research.

Graphical Abstract

Keywords

mesenchymal stem cells cigarette smoke conventional cigarettes proliferation viability differentiation immunomodulation toxicity regenerative medicine

Introduction

In the 1970s, Friedenstein et al.¹ identified mesenchymal stem cells (MSCs) as spindle-shaped, adherent, non-hematopoietic stem cells located in bone marrow.² Subsequent research has identified the presence of MSCs in various tissues, including adipose tissue, umbilical cord, and dental pulp^3,4. Afterward, Pittenger et al.⁵ found that MSCs can be induced to differentiate specifically into adipocytes, chondrocytes, or osteoblasts. In addition to their notable self-renewal abilities, MSCs demonstrate significant potential for differentiation into diverse cell lineages (mesoderm lineages and, under certain conditions, into ectoderm and endoderm tissues), demonstrating significant developmental plasticity⁶. Studies indicate that MSCs demonstrate a reduced risk of tumorigenesis, as their differentiation pathway generally avoids malignant transformation, somewhat mitigating concerns related to the safety and side effects of stem cell therapies^7,8. Besides, MSCs demonstrate low immunogenicity attributed to the absence of MHC class I molecules and the costimulatory molecule CD40, as well as limited expression of MHC class II molecules, thereby decreasing the likelihood of rejection post-transplantation^9,10. Of note, a recent research has shown that MSCs possess considerable immunomodulatory capabilities^11–13. This positions them as an excellent tool in regenerative medicine and highly promising candidates for the treatment of autoimmune inflammatory disorders. The immunomodulatory mechanisms of MSCs are primarily mediated through interactions with immune cells, involving both direct cell contact and paracrine signaling¹⁴. Consequently, MSCs demonstrate significant potential for cell therapy in the treatment of diverse diseases in both human and animal models, contributing importantly to immunoregulation, anti-inflammatory responses, and tissue regeneration^15,16. In particular, concerning the role of MSCs in tissue homeostasis, it has been proposed that indirect effects, particularly those involving paracrine signaling that regulates neovascularization, proliferation, differentiation of adjacent stem cells, and immune responses, are more significant in tissue regeneration than direct differentiation in alignment with surrounding tissues^17–19. Likewise, experimental evidence indicates that paracrine effects are mediated by extracellular vesicles (EVs), which encompass a range of intracellular bioactive and signaling molecules secreted by MSCs. Therefore, the use of EVs or secretomes has surfaced as a viable alternative to mitigate the risks associated with live-cell therapies^20–23. Considering all of the mentioned traits of MSCs and their excellent potential in regenerative medicine, it is of paramount importance to appraise the impact of environmental factors that may impede their regenerative capacity. Despite a decline in global smoking prevalence, tobacco use remains widespread, contributing to a substantial health burden globally, with one billion individuals smoking regularly and resulting in 7.0 million deaths in 2020²⁴. Cigarette smoke contains toxic components that are absorbed into the bloodstream via the lungs and subsequently distributed to various organs, impairing their function²⁴. Furthermore, cigarette smoke, which contains toxins that induce oxidative stress and inflammation, plays a significant pathogenic role in the progression of various diseases²⁵. Besides, cigarette smoke contains hazards that are distributed to the bone marrow, negatively affecting hematopoiesis by impairing the proliferation and differentiation of hematopoietic stem cells (HSCs)²⁶. Like HSCs, MSCs located in the lungs, liver, kidneys, gut, brain, and bone marrow are similarly impacted by cigarette smoke due to their continuous exposure to toxins present in cigarette smoke. The research consistently indicates that exposure of MSCs to cigarette smoke may impair proliferation, differentiation potential, migratory capacity, immunomodulatory properties and finally, overall therapeutic efficacy of MSCs^23,27–33. These findings have serious repercussions for regenerative medicine and underscore the necessity of evaluating patient exposure history in cell-based therapies. Hence, the purpose of this review is to provide an up-to-date understanding of the impact of cigarette smoke on MSCs function.

Chemical composition of cigarette smoke

Tobacco smoke contains numerous complex combustion compounds. Research indicates the presence of 7357 chemical constituents, of which approximately 70 compounds have been validated as having carcinogenic activity^34–36. It is impracticable to measure all 7357 components for product monitoring and regulatory compliance. Therefore, it is imperative to choose a list of smoke constituents that has a suitably extensive chemical, pharmacological, and toxicological profile³⁷. Hoffmann et al. have released multiple lists enumerating diverse toxicologically and physiologically active components of mainstream smoke, recognized as Hoffmann analytes by both the tobacco industry and regulatory bodies^38–40. The Hoffmann analytes comprise 44 hazardous smoke components, excluding tar, nicotine, and carbon monoxide, categorized into nine classes: ammonia, aromatic amines, polycyclic aromatic hydrocarbons (PAH), phenols, carbonyls, hydrocyanic acid, nitrosamines, inorganic elements, and other volatile organics^38,40. Moreover, a subsequent study by Talhout et al.³⁷ enumerates 98 hazardous smoke components. Hence, these constituents include many chemical types such as alkaloids, aldehydes, nitrosamines, heavy metals, volatile organic compounds, and free radicals^37,39,41,42. The concentration and biological activity of these compounds differ based on tobacco type, cigarette design, and smoking patterns; however, their cumulative effect consistently indicates significant cellular toxicity^43,44. All of these ingredients are generated during combustion and include gas-phase and particulate-phase, interacting synergistically to elicit biological effects on all of the tissues and cells^27,37,45. Consequently, the gaseous phase can permeate the pulmonary alveolar epithelium, enter the bloodstream, and potentially engage directly with MSCs present in the circulation and tissues⁴⁵. Toxic Compounds in cigarette smoke and their effects on MSCs were summarized in Table 1.

Table 1.

Toxic compounds in cigarette smoke and their effects on MSCs.

Toxic compound	Concentration/presence	Mechanism of action on MSCs	Specific effects on MSCs	Citations
Nicotine	Primary chemical constituent	Binds to nAChRs (α7, α4β2 subunits); activates MAPK/ERK, PI3K/AKT, JAK/STAT pathways	Dose-dependent: low doses enhance proliferation, high doses (>3 mM) cause toxicity and apoptosis	Greenberg et al.²⁹
Formaldehyde	0.7–54.9 µg per cigarette	Disrupts cellular transport; increases ROS production; causes oxidative stress	Diminished epithelial sodium channel activity; membrane depolarization; sustained oxidative stress	Salah et al.²³, Park et al.⁴⁶ and Li et al.⁴⁷
Acetaldehyde	36.7–1199.5 µg per cigarette	Highly reactive electrophilic compound; formed during tobacco pyrolysis	Variable effects based on sugar content in tobacco and smoking practices	Wahl et al.⁴⁸ and Tulen et al.⁴⁹
Acrolein	1.3–121.7 µg per cigarette (most harmful aldehyde)	Most detrimental aldehyde; highly reactive electrophilic properties	Most extensively researched; highest hazard ranking among aldehydes	Weng et al.⁵⁰ and Tulen et al.⁴⁹
NNK (Nitrosamine)	Significant carcinogen in tobacco smoke	Forms DNA adducts through metabolism; causes genetic changes	Potential impairment of MSC functionality through irreversible genetic changes	Weng et al.⁵⁰ and Wang et al.⁵¹
NNN (Nitrosamine)	Significant carcinogen in tobacco smoke	Forms DNA adducts through metabolism; causes genetic changes	Potential impairment of MSC functionality through irreversible genetic changes	Weng et al.⁵⁰ and Wang et al.⁵¹
Cadmium	Heavy metal in significant concentrations	Impedes osteogenic development; affects ALP activity	Reduced collagen synthesis; oxidative stress; metabolic disturbances in BM-MSCs	Wu et al.⁵² and Abnosi and Golami⁵³
Lead	Heavy metal in significant concentrations	Bioaccumulation in tissues; systemic distribution to MSC populations	Direct exposure through respiratory tract; systemic distribution	van Strijp et al.³⁹ and Shakoori and Ahmad⁴²
Chromium	Heavy metal in significant concentrations	Bioaccumulation in tissues; systemic distribution to MSC populations	Direct exposure through respiratory tract; systemic distribution	van Strijp et al.³⁹ and Shakoori and Ahmad⁴²
Nickel	Heavy metal in significant concentrations	Higher levels in imported brands; bioaccumulation effects	Varies between cigarette brands and origins	van Strijp et al.³⁹, Shakoori and Ahmad⁴², Pennings et al.⁴³ and Marcilla et al.⁴⁴

nAChRs: nicotinic acetylcholine receptors; MAPK/ERK: Mitogen-Activated Protein Kinase Extracellular Signal-Regulated Kinase; PI3K/AKT: Phosphoinositide 3-kinase/Protein kinase B; JAK/STAT: Janus kinase/signal transducer and activator of transcription.

Primary toxic compounds of cigarette smoke affecting MSCs function

Nicotine

Nicotine is the primary chemical constituent of cigarette smoke, existing as acid salts that are absorbed in the lungs and regarded as a key factor in cigarette smoking addiction^54,55. Moreover, prior research has demonstrated that nicotine enhances proliferation, invasion, and angiogenesis while inhibiting apoptosis in cancer cells^56–58. On top of that, nicotine has been shown to adversely impact stem cells. Thus, whole cigarette smoke extract (CSE) and nicotine have been demonstrated to adversely affect the regenerative capacity of MSCs^48,59–62. The mechanisms involve direct cellular contact through nicotinic acetylcholine receptors, leading to altered intracellular signaling pathways that compromise vital cellular functions^63,64. Li et al.’s research underscores the adverse effects of nicotine on human umbilical cord mesenchymal stem cells (hUC-MSCs), illustrating that nicotine induces toxicity and apoptosis while simultaneously augmenting their migratory and stem-like characteristics. The alterations in hUC-MSCs, including elevated IL-6 levels and modifications in epithelial-mesenchymal transition markers, indicate the potential role of nicotine in promoting cancer progression⁶³. A study by Alkam and Nabeshima⁶⁵ displayed that nicotine, along with its oncogenic derivatives NNK and NNN, activates various intracellular signaling pathways by binding to nicotinic acetylcholine receptors (nAChRs) and β-adrenergic receptors (β-ARs). The homomeric α7 and heteromeric α4β2 subunits of nAChR are regarded as the principal receptors facilitating nicotine’s effects on the cell cycle⁶⁵. The expression of both subunits is significantly elevated in response to tobacco smoke-specific nitrosamine or nicotine⁶⁵. MSCs express the functional α7 subunit of the nicotinic acetylcholine receptor (nAChR). Nicotine exposure significantly elevates intracellular calcium levels in MSCs, resulting in the activation of calcium-dependent intracellular pathways and modifications to the cell cycle in MSCs exposed to nicotine⁶⁶. The interaction of nitrosamine or nicotine with nAChRs activates the MAPK/ERK, PI3K/AKT, and JAK/STAT signaling pathways, facilitating the development and proliferation of MSCs⁶⁶. Additionally, nicotine binds to nAChRs, activating Src kinase in a β-arrestin-1-dependent manner, which subsequently inactivates the Rb protein. Also, E2F1 regulation enhances the activity of proliferative genes⁶⁷. The nicotine/nAChR axis regulates the growth and proliferation of MSCs through its impact on the MAPK/ERK, PI3K/AKT, JAK/STAT, and Src/E2F1 signaling pathways⁶³. Shen et al.⁶⁰ noted a significant enhancement in the proliferation rate of bone marrow-derived mesenchymal stem cells (BM-MSCs) upon exposure to 50 to 100 nM nicotine over duration of 7 days. Kim et al.⁵⁹ demonstrated that nicotine concentrations ranging from 1 to 100 µM did not promote the proliferation of alveolar BM-MSCs. Consequently, this study displayed that only nicotine concentrations between 1 and 2 mM could enhance proliferation, while higher concentrations exceeding 5 mM failed to induce optimal proliferation of BM-MSCs⁵⁹. Zeng et al.⁶⁸ documented similar findings, indicating a dose-dependent decrease in proliferation and an elevation in apoptosis of human UC-derived MSCs subsequent to exposure to 0.5 to 1.5 mg/ml nicotine (3–9 mM). Nicotine’s negative effects on the growth of MSCs are due to its ability to cause oxidative stress and G0 cell cycle arrest in rapidly growing cells at high concentrations (>3 mM)⁶³. A significantly increased proliferation rate was observed in nicotine-exposed MSCs cultured in growth medium supplemented with antioxidant vitamin C⁶⁰. Ng et al.⁶⁹ conducted a later study indicating that the proliferation rate of MSCs derived from chronic smokers was 2.5 times lower than that of MSCs from non-smokers. Furthermore, a diminished proliferation ability was noted in MSCs after 3–5 passes, signifying that the detrimental effects of extended nicotine exposure were enduring and transmitted throughout successive generations. The findings indicate that a comprehensive history of nicotine use must be accurately assessed for all potential MSC donors to prevent the transplantation of MSCs with diminished proliferative capacity.

Formaldehyde and aldehydes

Among the numerous chemicals, nine toxicants have been prioritized for reduction by the WHO Study Group on TobReg^37,70. Components include those in the particulate phase, such as specific nitrosamines and benzo(a)pyrene, as well as those in the volatile phase, including aldehydes (e.g. acetaldehyde, acrolein, formaldehyde), volatile organic compounds (e.g. benzene, 1,3-butadiene), and carbon monoxide^37,70. The predominant chemical class of aldehydes includes acetaldehyde, acrolein, and formaldehyde. Short-chain aldehydes are formed during the pyrolysis and combustion of tobacco and are characterized as highly reactive electrophilic compounds due to their chemical structure. These aldehydes exhibit analogous mechanisms of formation, molecular structures, and chemical properties, potentially representing the wider chemical class of aldehydes found in smoke^49,50,71. The risk assessment of the three individual aldehydes, utilizing computer models that consider inhalation exposure risk factors, led to the establishment of a hazard ranking. The ranking determined that acrolein, the most extensively researched aldehyde, is the most detrimental component among the three^72,73. According to Talhout et al.,⁷⁴ the concentration of aldehydes in cigarette smoke is influenced by various factors, including the inclusion of added sugars in tobacco, smoking techniques, and the design of the cigarette. A study by Pauwels et al. has demonstrated the influence of these features on the quantity of aldehydes present in each cigarette^74–78. Research indicates a significant correlation between the sugar content in tobacco, particularly sucrose and glucose, and the production of formaldehyde^74,75. Higher sugar levels in tobacco may result in increased formaldehyde release, thereby enhancing the toxicity of MSCs. Also, numerous studies displayed that prolonged exposure to the formaldehyde elevates the production of ROS^42,79,80 resulting in sustained oxidative stress that may adversely affects the viability and functionality of MSCs⁸¹. Nonetheless, it is important to acknowledge that there is no research that directly investigates the impact of aldehydes on MSCs, so future research is mandatory to comprehensively understand this interaction.

Tobacco-specific nitrosamines

Tobacco and tobacco smoke include over 80 carcinogens. The tobacco-specific N-nitrosamines (TSNAs) 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N′-nitrosonornicotine (NNN) are significant carcinogens responsible for lung, oral cavity, and esophageal cancers in smokers⁸². Nitrosamines often present in tobacco products and smoke, such as N-nitrosodimethylamine (NDMA) and N-nitrosopyrrolidine (NPYR), typically exhibit low concentrations. NNN and NNK, conversely, are consistently present in significantly greater quantities. NNK and NNN are primarily synthesized by nitrosating their precursor amines, specifically tobacco pseudooxy nicotine and nornicotine^51,83. Nitrosation of nicotine 1, a prevalent tobacco alkaloid, can also lead to their formation⁸⁴. In the United States, tobacco consumption is the primary route of N-nitrosamine exposure. Individuals who smoke daily acquire significantly more than those who consume alcohol, food, or water⁸⁵. The main tobacco-specific N-nitrosamines, such as NNN, NNK, NAT, and NAB, are associated with the formation of DNA adducts via their metabolism⁸⁴, resulting in irreversible genetic changes that may impair the functionality of MSCs over time. It is crucial to acknowledge that contemporary research lacks direct examinations of the precise effects of tobacco-specific nitrosamines on MSCs. Consequently, subsequent investigations concentrating on this link may produce conclusive results.

Heavy metals

Cadmium, nickel, lead, and chromium are hazardous heavy metals present in elevated concentrations in cigarette smoke^52,86,87. These metals accumulate in tobacco smoke condensate and cigarette ash with their concentration being contingent upon its origin. A research by Ajab et al.⁴¹ indicates that imported brands contain higher levels of nickel compared to domestic brands. Wu et al.⁵² demonstrate that the concentrations among various brands differ markedly, and that there exists a statistically significant difference among different types of cigarettes. Pourkkhabbaz and Pourkhabbaz⁸⁶ observed that imported products may contain greater concentrations of certain metals compared to local brands. Nonetheless, this does not apply universally to all metals or in all locations. Anyways, the presence of these metals in tobacco smoke condensate and cigarette ash is a documented phenomenon, with research indicating notable bioaccumulation in diverse biological tissues after exposure^53,87. The presence of these metals in mainstream smoke guarantees direct exposure of respiratory tract tissues and subsequent systemic distribution to MSCs populations across the body. Although direct research connecting heavy metals in cigarette smoke to MSC damage is scarce^52,53. Recent research by Abnosi et al. that focused on the impact of cadmium on bone marrow mesenchymal stem cells (BM-MSCs) showed that cadmium impedes the osteogenic development of BM-MSCs, influencing ALP activity and collagen synthesis, with these effects being facilitated by oxidative stress and metabolic disturbances, therefore offering a potential mechanism by which heavy metals may impede the function of MSCs^42,53.

The impact of cigarette smoke on MSCs functions

Numerous studies indicate that exposure to cigarette smoke markedly disrupts the functionality of MSCs^{23,29,31,88,89}. Principal research findings regarding the effects of cigarette smoke on MSCs were summarized in Table 2. Exposure to cigarette smoke results in diminished regenerative capacity, characterized by reduced proliferation and viability, migration, and differentiation potential of exposed MSCs as well as detrimental impact on their immunomodulatory properties as shown in Fig. 1, indicating that smoking is a significant risk factor frequently neglected in cell-based therapeutic screening protocols, therefore raising significant concerns for clinical applications.

Table 2.

Principal research findings regarding the effects of cigarette smoke on MSCs.

Research group	Year of publication	Studied MSC type	Principal conclusions	The significance of clinical implications.	Type of study
Salah et al.²³	2024	ADMSCs	Increased expression of oxidative stress-related genes; diminished expression of metabolic genes; reduced cell proliferation and viability.	Smoker MSCs exhibit diminished therapeutic potential for regenerative medicine.	In vivo
Riad et al.⁸⁸	2024	DPSCs	CSE exposure resulted in decreased proliferation rates, lower ALP activity, and diminished RANKL expression.	The efficacy of MSCs in dental or oral applications may be diminished in smokers.	In vitro
Kastratovic et al.³¹	2024	PDL-MSCs	Combustible cigarettes resulted in more significant impairment compared to electronic nicotine delivery systems.	Traditional cigarettes present a higher risk compared to alternative tobacco products.	In vitro
Uriciuc et al.⁹⁰	2025	Oral cavity MSCs	Harmful compounds detected via LC-MS and FT-IR; decreased pH and increased cytotoxicity	Oral cavity homeostasis significantly disrupted by tobacco residues	In vitro
Aspera-Werz et al.⁹¹	2019	SCP-1 cells	CSE inhibited TGF-β signaling, leading to decreased phosphorylation of Smad2/3 and reduced nuclear translocation.	Impaired fracture healing observed in individuals who smoke.	In vitro
Wahl et al.⁴⁸	2016	AT-MSCs	High concentrations of CSE (>5%) resulted in metabolic inactivity, while low concentrations (<1%) exhibited minimal effects.	Effects that depend on dosage are crucial for considerations in clinical applications.	In vitro
Tura-Ceide et al.⁸⁹	2017	BM-MSCs	Mice exposed to CS exhibited diminished engraftment capacity, along with decreased proliferation and migration.	Decreased therapeutic efficacy of MSCs in respiratory diseases	Both in vivo and in vitro
Ng et al.⁶⁹	2015	PDL-MSCs	A 2.5-fold decrease in the proliferation rate of MSCs was observed in chronic smokers compared to non-smokers.	The effects of long-term smoking endure through various cell passages.	In vitro
Cruz et al.⁹²	2019	LR-MSCs	Cigarette smoking markedly diminished the immunomodulatory capacity of LR-MSCs in patients with COPD.	Smoking cessation has the potential to restore the immunomodulatory function of mesenchymal stem cells (MSCs).	In vivo
Park et al.⁴⁶	2024	hMSCs	Exposure to 3R4F resulted in increased inflammation, accelerated aging, enhanced wound repair, and elevated ROS, as well as activation of the NLRP3 inflammasome.	Identified comprehensive molecular mechanisms for therapeutic targeting.	Both in vivo and in vitro

ADMSCs: adipose-derived MSCs; DPSCs: dental pulp stem cells; PDL-MSCs: periodontal ligament MSCs; SCP-1: single-cell human mesenchymal cell line; AT-MSCs: adipose tissue-derived MSCs; BM-MSCs: bone marrow MSCs; LR-MSCs: lung-resident MSCs; ROS: reactive oxygen species; NLRP3: NLR family pyrin domain containing 3 inflammasome; hMSCs: human MSCs; RANKL: receptor activator of nuclear factor kappa-B Ligand.

Figure 1.

The impact of cigarette smoke on MSCs functions. This figure illustrates how exposure to cigarette smoke results in diminished regenerative capacity, characterized by reduced proliferation and viability, migration, and differentiation potential of exposed MSCs as well as detrimental impact on their immunomodulatory properties. MSCs: mesenchymal stem cells; TGF-β: Transforming Growth Factor beta; CTTN: cortactin; BIRC5: surviving; CXCL9: C-X-C motif chemokine ligand 9; NLRP3: NLR family pyrin domain containing 3 inflammasome; Created with CorelDraw.

The impact of cigarette smoke on MSCs’ proliferation and viability

Numerous studies are consistent among MSCs subtypes, indicating that cigarette smoke universally impairs the proliferative potential of MSCs^88,89,93. These studies demonstrate that both acute and chronic exposure hinder proliferation of MSCs, with proliferation impairment being directly tied to smoke concentration^88,89,93. A recent study by Salah et al.²³ demonstrates that cigarette smoke significantly impacts the proliferation, survival, and functionality of adipose-derived mesenchymal stem cells (ADMSCs) in smokers relative to non-smokers. ADMSCs obtained from smokers exhibited elevated expression of oxidative stress response genes (e.g. HMOX1, SOD2) and reduced expression of metabolic genes (e.g. PPARG, CAT), hence hindering proliferative pathways²³. Moreover, the same study indicates a marked reduction in cell proliferation and viability among smokers, accompanied by evidence of apoptosis and DNA damage while analysis of gene expression indicates an increased expression of oxidative stress response genes and a decreased expression of genes associated with inflammation and metabolism²³. Of note, mitochondrial membrane potential (MMP) was stable in ADMSCs from smokers; however, apoptosis assays indicated decreased viability through alternative pathways, including p53/p21-mediated cell cycle arrest as shown in Fig. 1. A recent study conducted by Riad et al.⁸⁸ on dental pulp stem cells (DPSCs) substantiates this finding, demonstrating that exposure to cigarette smoke extract (CSE) led to diminished proliferation rates in comparison to control cells. Further, a recent study by Kastratovic et al.³¹ found that combustible cigarettes induced viability and proliferation impairment in PDL-MSCs, which was greater when compared to electronic nicotine delivery systems (ENDS). Thus, the latest study by Uriciuc et al.⁹⁰ demonstrates the negative effects of cigarette smoking on oral cavity homeostasis, particularly through an analysis of tobacco residues and their influence on MSCs. The detection of harmful compounds in CSEs, demonstrated through LC-MS and FT-IR analyses, is associated with a decrease in pH and an increase in cytotoxicity in MSCs, resulting in notable morphological alterations and diminished cell viability⁹⁰. In addition, a study by Tura-Ceide et al.⁸⁹ demonstrated that exposure to CSE diminished the proliferative capacity of guinea pig BM-MSCs, exhibiting dose-dependent effects in vitro. Besides, a study by Aspera-Werz et al.⁹¹ demonstrates the substantial influence of CSE on TGF-β signaling in MSCs, clarifying a key mechanism that contributes to the impaired fracture healing seen in smokers. CSE exposure diminished the phosphorylation of Smad2/3 and the nuclear translocation of Smad3/4, which are essential for TGF-β-mediated proliferation and differentiation⁹¹. This effect occurred downstream of the ALK5 receptor, indicating direct interference with cell cycle regulators⁹¹ Molecular pathways and biomarkers affected by cigarette smoke in MSCs were summarized in Table 3, though it should be noted that that the list in is not exhaustive, while specific mechanistic details in MSCs require more targeted research. Besides, a study by Abate et al.⁹⁴ found that the structure and strength of cartilage deteriorates following prolonged exposure to cigarette smoke. In accordance with that, a study by Chen et al.⁹⁵ found that cigarette smoke reduces chondrocyte proliferation and adversely impacts cartilage metabolism through the downregulation of COL1A1 expression. COL1A1 is highly expressed in MSC-derived chondrocytes, which plays a big role in MSC-mediated repair and regeneration of damaged cartilage⁹⁶. Wahl et al.⁴⁸ utilized a metabolic activity assay to evaluate the viability of adipose tissue-derived mesenchymal stem cells (AT-MSCs) after exposure to different concentrations of CSE. No changes in metabolism or cell viability were observed in AT-MSCs exposed to low (<1%) concentrations of CSE for 48 h⁴⁸. Nearly all AT-MSCs subjected to 5% or 10% CSE exhibited metabolic inactivity or non-viability. In the aftermath, this research provided strong evidence that cigarette smoking, under certain conditions, adversely impacts the metabolism and viability of MSCs.

Table 3.

Molecular pathways and biomarkers affected by cigarette smoke in MSCs.

Pathway or biomarker	Function/normal role	Effect of cigarette smoke	Impact on MSCs	Citations
TGF-β/Smad signaling pathway	Regulates growth, differentiation, and alterations in the immune system	Reduced phosphorylation of Smad2/3 results in diminished efficacy of nuclear translocation	Decreased growth, differentiation, and therapeutic efficacy of MSCs	Aspera-Werz et al.⁹¹
The MAPK/ERK pathway	Regulates cellular growth and survival	Dysregulated activation and altered cell cycle regulation	Impaired regulation of the cell cycle and growth capacity	Greenberg et al.²⁹ and Alqithami et al. ⁹⁷
Pathway of PI3K/AKT signaling	Promotes cellular survival and proliferation	Disruption of cell survival signaling	Reduced cell viability and lifespan	Greenberg et al.²⁹
JAK/STAT Signaling Pathway	Enhances cytokine signaling and immune responses	Altered cytokine production and immune system function	Pro-inflammatory phenotype; reduced immunosuppressive capacity	Pavlovic et al.²⁸, Greenberg et al.²⁹, Li et al.⁶³, Schraufstatter et al.⁶⁶ and Hoogduijn et al.⁶⁷
NLRP3 Inflammasome	Regulates the body’s response to inflammation	Activation increased the production of inflammatory cytokines	Heightened inflammation; reduced therapeutic effectiveness	Park et al.⁴⁶
The miRNA-1305 and RUNX2 Interaction	Regulates the differentiation of osteogenic cells	RUNX2 activity and osteoblastogenesis disrupted and diminished	Reduced bone formation and impaired osteogenic differentiation	Ng et al.⁶²
Signaling pathways involving CD44 and CTTN	Regulates cellular movement and invasion	Reduced CD44 expression; decreased transcription of CTTN and BIRC5	Reduced capacity for migration and settlement	Ouhtit et al.⁹⁸
Cx43	Facilitates communication through gap junctions and contributes to bone remodeling	Deficiency following CSE exposure; compromised cellular communication	Repair of damaged tissue and potential for osteogenesis	Aspera-Werz et al.⁹¹
Indicators of Oxidative Stress	Maintains redox balance in cells	Elevated ROS production leads to prolonged oxidative stress	Cellular damage, apoptosis, and functional impairment	Aspera-Werz et al.¹⁰⁰, Volarevic et al.⁹⁹, Zhang et al.¹⁰¹, Seo et al.¹⁰²

TGF-β: Transforming Growth Factor beta; MAPK/ERK: Mitogen-Activated Protein Kinase Extracellular Signal-Regulated Kinase; PI3K/AKT: Phosphoinositide 3-kinase / Protein kinase B; JAK/STAT: Janus kinase/signal transducer and activator of transcription; NLR family pyrin domain containing 3 inflammasome; RUNX2: Runt-related transcription factor 2; CTTN: cortactin; BIRC5: surviving; CXCL9: C-X-C motif chemokine ligand 9; Cx43: Connexin 43.

The impact of cigarette smoke on MSCs’ migration

Numerous studies have displayed that cigarette smoke has detrimental effects on the migratory potential of MSCs^48,89,93, which is essential for their homing to sites of tissue injury and inflammation (Fig. 1). Thus, a study by Wahl et al.⁴⁸ found that constant exposure to high concentrations of CSE resulted in lethal effects on AdMSCs, whereas lower concentrations of CSE hindered cell migration relative to control conditions. Notably, the concentration of CSE exceeding 5% markedly reduced the expression of chemokine receptors on AT-MSCs and compromised their homing capabilities⁴⁸. However, the migratory properties of AT-MSCs remained unchanged when exposed to low concentrations (below 1%) of CSE. Tura-Ceide et al.⁸⁹ conducted additional research that demonstrated BM-MSCs derived from CS-exposed mice had compromised engraftment capacity, along with reduced proliferation and migration rates. In vitro, BM-MSCs treated with CS extract exhibited a marked decrease in their capacity for proliferation, differentiation, and migration⁸⁹. The research conducted by Aspera-Werz et al.⁹¹ underscores the critical function of CSE in modulating the TGF-β signaling pathway, particularly for its influence on phospho-Smad2/3 levels and the nuclear translocation of Smad3/4. These findings elucidate the mechanisms through which TGF-β signaling dysregulation partially contributes to the adverse consequences reported in MSC migration. Recent research by Heikkinen et al.⁹³ shows that MSCs exposed to CSE had less effective wound healing and higher cell death rates at higher concentrations of cigarette smoke. At lesser concentrations, CSE also halted osteogenic differentiation, migration, and proliferation⁹³ (Fig. 1 and Table 3). Ouhtit et al.’s⁹⁸ research elucidates the significance of CD44 in preventing the migration and invasion of MSCs in cigarette users. It further demonstrates that CD44 simultaneously regulates the transcription of cortactin (CTTN) and survivin (BIRC5). This study demonstrated that cigarette smoke condensate reduces the expression of CD44 and its downstream targets, CTTN and BIRC5, in MSCs, with CTTN specifically recognized as a sign of cellular motility⁹⁸. Hence, the disruption of these pathways directly impacts the cellular mechanisms required for appropriate chemotactic responses. These findings indicate that one must exercise caution when considering smokers’ MSCs for cell therapy, as they may be linked to the development of conditions such as osteoporosis, lung injury, and emphysema. Additionally, the identification of CD44/CTTN and CD44/BIRC5 signaling pathways provides fresh opportunities to develop therapeutic strategies targeting cancer and other diseases associated with CD44. Besides CD44, other molecules involved in the migration of MSCs must be considered. Consequently, C-X-C motif chemokine ligand 9 (CXCL9) is expressed by circulating BM-MSCs and is recognized for its significant role in their migration through the endothelium^103,104. In line with that, a study by Tura-Ceide et al.⁸⁹ found that CXCL9 expression levels were diminished in the bone marrow of animals exposed to cigarette smoke when compared to the control group. Therefore, this signaling pathway plays a role in the homing of BM-MSCs and is negatively affected by cigarette smoke. Furthermore, a recent study conducted by Park et al.⁴⁶ demonstrated that direct ex vivo and systemic in vivo exposure of MSCs to 3R4F cigarettes resulted in compromised engraftment in a humanized mouse model. Moreover, transcriptomic profile analysis demonstrated a pronounced up regulation of signaling pathways related to ROS, inflammation, and aging in MSCs exposed to 3R4F cigarettes, while ingenuity pathway analysis revealed the activation of the NLRP3 inflammasome signaling pathway in 3R4F-treated MSCs⁴⁶. Withal, pretreatment with the NLRP3 inhibitor MCC950 restored the hematopoietic stem and progenitor cells (HSPCs)-supporting capacity of 3R4F-treated MSCs⁴⁶. These findings indicate that exposure to CSE reduces HSPCs’ supportive function of MSCs by inducing robust ROS production and subsequent NLRP3 activation, thereby impairing HSPC engraftment.

The impact of cigarette smoke on MSCs’ differentiation potential

It is widely recognized that cigarette smoke significantly impairs the capacity of MSCs to differentiate into various cell types as shown in Fig. 1; yet, acute exposure does not influence adipogenic differentiation^48,64,91,93. Various research teams have effectively illustrated that the adverse impacts of cigarette smoke and nicotine on the osteogenic differentiation of MSCs are mostly responsible for the impaired osteogenesis observed in cigarette smokers^61,62,100. Ng et al.⁶² reported a notable reduction in alkaline phosphatase (ALP) expression, reduced calcium accumulation, and altered miRNA-1305 expression in MSCs derived from smokers’ PL-MSCs. They hypothesized that the diminished osteogenic ability of smokers’ MSCs results from the detrimental effects of cigarette smoke on the miRNA-1305/Runt-related transcription factor 2 (RUNX2) axis, given that miRNA-1305 regulates RUNX2 activity, which is crucial for osteoblast development⁶². Additionally, the latest study by Hekkinen et al.⁹³ assessed ALP activity and calcium deposition in the extracellular matrix to evaluate the effects of nicotine and CSE exposure on the osteogenic differentiation of MSCs (as shown in Fig. 1 and Table 3). They found that CSE diminished osteogenic differentiation of MSCs in vitro⁹³. Also, the latest research by Raid et al.⁸⁸ analyzed how CSE affects the proliferation and osteogenic differentiation of dental pulp stem cell (DPSCs). It is well established that RANKL plays a vital role in bone remodeling by regulating the activities of osteoblasts and osteoclasts involved in bone production and resorption. Thus, they demonstrated that DPSCs treated with IC50 TE-p and e-Cig-LV exhibited a significant reduction in ALP activity levels and a significant reduction in RANKL expression relative to control cells⁸⁸. The results align with the findings of Sreekumar et al.,¹⁰⁵ which indicated that treatment of human MSCs with CSE significantly inhibited RANKL production, potentially impacting overall bone stability. CSE may also impede bone healing by inhibiting the early osteogenic differentiation of MSCs and disrupting the equilibrium between mature osteoblasts and osteoclasts, thus affecting the bone remodeling processes in fractured bones. Notably, Zhang et al.¹⁰¹ assessed that the overproduction of ROS inhibits the osteogenic differentiation of BM-MSCs treated with smoke. Besides, data from various studies indicate that the reduction in osteogenic differentiation may be attributed to Cx43, the principal connexin found in MSCs, which plays a direct role in osteogenic remodeling¹⁰⁶. The deficiency of Cx43 following exposure to CSE is associated with a decrease in osteogenic differentiation potential and disruption of cell communications via gap junctions, which are closely tied to the modulation of repair mechanisms. Numerous studies have demonstrated that gap junctions are critical for the prevention of oxidative stress-induced cell death¹⁰⁷. As such, exposure to cigarettes may impair tissue repair¹⁰⁸. Wahl et al.⁴⁸ found that cigarette smoke notably impacted the osteogenic and chondrogenic differentiation capabilities of MSCs. Appropriately, they demonstrated the negative impact of cigarette smoke on the chondrogenic differentiation of MSCs. Exposure to 0.5% CSE significantly altered the expression of cartilage-specific proteoglycan core protein (CSPCP) and the chondrogenic transcription factor SOX9 in MSCs⁴⁸. The down-regulation of COL1A1 expression in CSE-exposed MSCs suggests that the adverse effects of cigarette smoke on the chondrogenic potential of MSCs may contribute significantly to increased cartilage loss and delayed healing in injured cartilage, commonly seen in cigarette smokers^48,94. However, it should be noted that MSCs exposed to CSE exhibited no significant changes in adipogenic differentiation⁴⁸, suggesting that the signaling pathways regulating adipogenic differentiation in MSCs remained largely unaffected by cigarette smoke. Not just osteogenic, chondrogenic, but also cardiac differentiation of MSCs can be affected by cigarette smoke. Particularly, a recent study by Gheisari et al.⁶⁴ displayed that nicotine exerts an inhibitory effect on cardiac differentiation of MSCs. Thus, the expressions of two cardiac-specific markers were examined. Accordingly, GATA4, which was expressed at the early stages of cardiac differentiation, was significantly downregulated on day 3 in MSCs⁶⁴. This was the case for troponin as well, which is a late cardiac marker. However, increased expression of both GATA4 and troponin on day 7 may be explained by the decreasing effect of nicotine after 7 days. It seems that, similar to proliferation, there is a threshold of nicotine concentrations for affecting the differentiation potential of MSC. This factor holds significant importance for smokers eligible for stem cell therapy due to cardiovascular disease.

The impact of cigarette smoke on MSCs’ immunomodulatory potential

MSCs do not exhibit constitutive immunosuppressive properties¹⁰⁹. The phenotype and function of MSCs can be influenced by endogenous factors and environmental hazards^27,109. When MSCs are transplanted into inflamed tissues characterized by elevated levels of inflammatory cytokines, they acquire an immunosuppressive phenotype and secrete anti-inflammatory cytokines, leading to a reduction in ongoing inflammation. On the other hand, when MSCs are exposed to low levels of inflammatory cytokines, they adopt a pro-inflammatory phenotype, resulting in the production of significant amounts of TNF-α and IFN-γ, which exacerbates inflammation¹⁰⁹. Hence, the local tissue microenvironment, particularly the concentration of inflammatory cytokines affecting MSCs exposure, influences the phenotype and immunoregulatory characteristics of MSCs. Similar to tissue microenvironments, environmental hazards, especially cigarette smoke, may influence the phenotype and function of MSCs²⁷, diminishing their therapeutic effects. In line with that, using α-galactosylceramide (α-GalCer)-induced liver injury, a recognized murine model of fulminant hepatitis, we investigated the molecular mechanisms underlying the adverse effects of cigarette smoke on MSC-dependent immunomodulation²⁸. MSCs that were cultured in cigarette smoke-exposed medium (MSC-WS-CM) induced a pro-inflammatory phenotype, resulting in suboptimal production of hepatoprotective and immunosuppressive cytokines (TGF-β, HGF, IL-10, NO, KYN)²⁸. Additionally, it led to significantly higher secretion of inflammatory cytokines (IFN-γ, TNF-α, IL-17, IL-6) compared to MSCs cultured in standard medium without cigarette smoke exposure (MSC-CM) as shown in Fig. 2. In contrast to MSC-CM, which effectively reduced α-GalCer-induced hepatitis, MSC-WS-CM did not prevent hepatocyte injury or liver inflammation. MSC-WS-CM exhibited diminished capacity to suppress liver-infiltrated inflammatory macrophages, dendritic cells (DCs), and lymphocytes. In α-GalCer+MSC-CM-treated mice, there was a significantly lower number of IL-12-producing macrophages and dendritic cells, as well as TNF-α, IFN-γ, or IL-17-producing CD4+ and CD8+ T lymphocytes, NK, and NKT cells in the liver compared to α-GalCer+saline-treated animals²⁸. However, this phenomenon was not observed in α-GalCer-injured mice that received MSC-WS-CM. The presence of inflammatory, IFN-γ and IL-17-producing NK cells and T lymphocytes was significantly reduced in the livers of α-GalCer+MSC-CM-treated mice. This reduction is attributed to MSC-derived TGF-β, which suppresses the activation of the Jak-Stat signaling pathway in activated T and NK cells, induces G1 cell cycle arrest, and inhibits the expansion of these hepatotoxic cells⁹⁹ (as shown in Table 3). We propose that the decreased production of TGF-β by MSC-WS-CM primarily contributed to the heightened presence of inflammatory NK cells and T lymphocytes in the livers of α-GalCer+MSC-WS-CM–treated animals, leading to subsequent NK and T cell-mediated hepatocyte injury. Also, MSC-WS-CM failed to promote the expansion of anti-inflammatory IL-10-producing FoxP3+CD4+ and CD8+T regulatory cells and did not establish an immunosuppressive microenvironment in the liver, unlike MSC-CM²⁸. As observed in mice, MSC-WS-CM did not effectively inhibit the production of inflammatory and hepatotoxic cytokines in activated human Th1/Th17 and NKT1/NKT17 cells²⁸. This supports the hypothesis that cigarette smoke significantly reduces the therapeutic potential of MSCs in cell-based immunotherapy for inflammatory liver diseases, as shown in Fig. 2. In line with that, Cruz et al.⁹² identified cigarette smoking as a significant behavioral risk factor that markedly reduces the immunomodulatory and therapeutic potential of MSCs. Cruz et al.⁹² analyzed the phenotype and function of lung-resident MSCs (LR-MSCs) obtained from current and former smokers with COPD, demonstrating that cigarette smoking significantly reduces the immunomodulatory capacity of LR-MSCs in these patients. Given that the transplantation of MSCs and their secretome effectively mitigates COPD in mice by inhibiting harmful T cell-mediated lung inflammation¹¹⁰, the impact of cigarette smoke on LR-MSC-mediated T cell inhibition was examined. CSE-exposed LR-MSCs demonstrated an inability to effectively suppress the proliferation of CD4+T helper cells and CD8+CTLs, as well as to inhibit the production of inflammatory cytokines in activated T lymphocytes in vitro⁹². Cruz et al. hypothesized that long-term exposure to cigarette smoke leads to increased synthesis of ROS and decreased activity of anti-oxidative enzymes in LR-MSCs. CSE-induced oxidative stress increases the expression of inflammation-related genes and induces the generation of a pro-inflammatory phenotype in MSCs⁴⁸. Pro-inflammatory MSCs exhibit increased production of inflammatory cytokines such as TNF-α, IL-1β, and IFN-γ, alongside diminished synthesis of immunosuppressive cytokines including IL-10, IL-35, and TGF-β¹⁰⁹. Additionally, they show a reduced ability to suppress activated T cells. The immunomodulatory properties of LR-MSCs in COPD patients were found to be impaired exclusively in current smokers, whereas the immunoregulatory functions of LR-MSCs in former smokers were comparable to those in healthy controls⁹². The findings indicate that the adverse effects of cigarette smoke on the immunosuppressive function of LR-MSCs are not permanent, and the immunosuppressive potential of LR-MSCs can be nearly fully restored following smoking cessation⁹². At the same time, numerous studies demonstrate that CSE leads to the overproduction of ROS, mitochondrial dysfunction, and oxidative stress in MSCs^{46,47,111–113}. Furthermore, CC-derived tar and carbon monoxide (CO) are known to induce oxidative stress, increase the release of ROS, and activate mitogen-activated protein kinase (MAPK) signaling cascades in immune cells exposed to combustible cigarettes, leading to increased production of inflammatory cytokines¹¹⁴ (Table 3). Accordingly, most recent study by Kastratovic et al.³¹ clarified the impact of various tobacco products on the intricate relationships between mesenchymal stem cells derived from periodontal ligament (PDL-MSCs) and T lymphocytes, essential for sustaining oral tissue homeostasis. Co-culturing T cells with PDL-MSCs exposed to combustible cigarette smoke resulted in an immune response marked by elevated levels of inflammatory IFN-γ and IL-17-producing CD4+ and CD8+ T cells³¹, as well as elevated synthesis of TNF-α and IFN-γ in PDL-MSCs (Table 2). This response may intensify bone resorption, thereby worsening damage to periodontal tissue. Moreover, the latest research by Park et al.,⁴⁶ using transcriptomic profiling, revealed that 3R4F exposure elevates inflammation, cellular aging, wound repair, and ROS in human mesenchymal stem cells (hMSCs). Hence, RNA sequencing was performed to examine the alteration of the transcriptomic profile of 3R4F-treated hMSCs⁴⁶. Gene set enrichment analysis (GSEA) using the gene ontology biological process (GO BP) gene sets identified four significantly upregulated categories in 3R4F-treated hMSCs: inflammatory response, aging, wound healing, and response to oxidative stress gene sets⁴⁶. The inflammatory response involved enriched gene sets with upregulated expression of NLRP3, IL-1β, and IL-6. To confirm the RNA-seq results, Park et al. assessed the expression levels of the proinflammatory genes NLRP3, IL-1β, IL-6, IL-8, and TNF-α by qRT-PCR. The 3R4F treatment enhanced the expression of proinflammatory genes in hMSCs⁴⁶. Similarly, they identified that IL-10 and IDO, known immunosuppressive factors of MSCs, were both downregulated by 3R4F treatment⁴⁶. Additionally, 3R4F inhibited the anti-proliferative effect of hMSCs on T lymphocytes. Collectively, they came to conclusion that 3R4F perturbs immune homeostasis by altering global gene expression patterns of hMSCs, with functional consequences demonstrated in vitro⁴⁶. Correspondingly, it should be noted that the relationship between oxidative stress and inflammation in cigarette smoke-exposed MSCs is bidirectional, with ROS serving both as initiators and amplifiers of inflammatory responses. The oxidative environment facilitates the activation of redox-sensitive transcription factors, including NF-κB, thereby increasing proinflammatory gene expression^97,115–117.

Figure 2.

The impact of cigarette smoke on MSCs immunomodulatory and hepatoprotective potential. This figure illustrates how exposure to cigarette smoke abrogates immunomodulatory and hepatoprotective potential of MSCs. MSCs that were cultured in cigarette smoke-exposed medium acquired a pro-inflammatory phenotype, resulting in significantly higher secretion of inflammatory cytokines (IFN-γ, TNF-α, IL-17, IL-6) and suboptimal production of hepatoprotective and immunosuppressive cytokines (TGF-β, HGF, IL-10, NO, KYN). MSCs: mesenchymal stem cells; IFN-γ: interferon gamma; TNF-α: tumor necrosis factor alpha; TGF-β: transforming growth factor beta; HGF: hepatocyte growth factor; NO: nitric oxide; KYN: kynurenine; Created with CorelDraw.

Research gaps and future directions

There is a considerable gap in the field in terms of the lack of standardized protocols for CSE preparation¹¹⁸. Especially having in mind that various research groups utilize differing methodologies, concentrations, and exposure durations, which in turn makes direct comparisons difficult¹¹⁹. Some scientists have come up with the virtual tar concentration approach, which could be a solution, but not many of the researchers are adopting it yet¹¹⁸. Therefore, consensus guidelines for physiologically pertinent exposure concentrations grounded in the actual nicotine and toxicant levels found in human smokers as well as standardized biomarkers to assess MSCs dysfunction in smokers should be developed^{23,46,93,120–122}. Moreover, the differing traits of MSCs isolated from various sources must be taken into consideration^23,88,120. Notably, the vast majority of the research focuses on in vitro studies when examining the impact of cigarette smoke on MSCs. This demands incorporation of clinical studies using MSCs isolated from actual smokers versus non-smokers to validate in vitro findings²³. Hence, it must be emphasized that in vivo studies using physiologically relevant exposure models can only offer definite conclusions regarding the impact of cigarette smoke on MSCs and mirror clinical scenarios^26,46,123. Finally, alternative tobacco products must be reconsidered, keeping in mind their less detrimental effect on MSCs^30,31,106, even though they are not risk-free⁸⁸. Future research ought to examine potential interventions to alleviate the effects of cigarette smoke on MSCs, including antioxidant therapies or targeted pathway inhibitors^46,124,125. Some studies suggest that certain compounds, such as vitamin C or specific inhibitors, can partially restore MSC function¹²⁶.

The donor’s smoking history and the recipient’s smoking status must be considered when using MSCs in regenerative medicine. Both aspects significantly influence the efficacy of treatment, albeit in distinct manners, and pose peculiar obstacles to regenerative medicine. Thus, MSCs derived from smokers exhibit significantly reduced growth rates, demonstrating a significant decrease in proliferation compared to non-smoking controls²⁹ as well as impaired functional capabilities such as migratory, differentiation, and proliferative potential⁴⁸. Moreover, studies comparing MSCs from diabetic smokers versus non-smokers reveal that smoking status significantly decreases glycolytic capacity and maximal mitochondrial respiration¹²⁷. This metabolic dysfunction directly impacts the cells’ synthetic function and overall therapeutic potential. Conversely, when MSCs are administered to smokers, they must contend with a modified milieu throughout the body, which complicates their functionality and viability, regardless of the initial health of the donor cells^27,29. In addition, it must be emphasized that defects originating from the donor occur singularly, whereas the recipient’s smoking habit continually exposes them to detrimental toxins^26,46,48. Hence, this persistent assault implies that even healthy transplanted MSCs will be compromised by the toxins consistently present in the body, which may exacerbate the therapeutic impact over time. The tissue environment in which MSCs must engraft and function is significantly altered by the recipient’s smoking history. As it has been recently displayed by a study of Siggins et al.,²⁶ exposure to cigarette smoke reduces the quantity of endogenous MSCs in the bone marrow niche, which makes the environment less supportive to transplanted cells. In a nutshell, only a thorough analysis of donors’ and recipients’ habits, particularly their smoking history, along with future and deeper research, can mitigate the obstacles regarding MSCs therapy.

Conclusion

As MSCs are an attractive regenerative medicine tool, and since their usage is increasing in preclinical and clinical studies, it is of paramount importance to assess all of the noxas that may impair their therapeutic efficacy. Yet, there is a significant gap in cigarette smoke exposure research, as varying methodologies, concentrations, and exposure durations complicate direct comparisons. It is essential to establish consensus guidelines for exposure concentrations relevant to physiological conditions and standardized biomarkers to evaluate MSC dysfunction in smokers. The inclusion of clinical studies utilizing MSCs from active smokers is essential for the validation of in vitro results.

Footnotes

Acknowledgements

Not applicable.

ORCID iDs

Dragica Pavlovic

Vladislav Volarevic

Ethical considerations and consent to participate

This manuscript is a review article and does not involve any ethical issues. All authors reviewed and approved the final version of the manuscript.

Statement of human and animal rights

This article does not contain any studies with human or animal subjects.

Statement of informed consent

There are no human subjects in this article and informed consent is not applicable.

Author contributions

D.P., D.P., and D.N. contributed to Conceptualization; Visualization; Writing – original draft; Writing – review & editing. V.V. supervised the study and provided critical feedback and revisions. All authors contributed to the finalization of the manuscript and approved the final version

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

All information in this review was obtained from previously published literature. Therefore, no new data were generated or analyzed, and all referenced data are publicly available.

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Impact of cigarette smoke on the functions of mesenchymal stem cells

Abstract

Keywords

Introduction

Chemical composition of cigarette smoke

Primary toxic compounds of cigarette smoke affecting MSCs function

Nicotine

Formaldehyde and aldehydes

Tobacco-specific nitrosamines

Heavy metals

The impact of cigarette smoke on MSCs functions

The impact of cigarette smoke on MSCs’ proliferation and viability

The impact of cigarette smoke on MSCs’ migration

The impact of cigarette smoke on MSCs’ differentiation potential

The impact of cigarette smoke on MSCs’ immunomodulatory potential

Research gaps and future directions

Conclusion

Footnotes

Acknowledgements

ORCID iDs

Ethical considerations and consent to participate

Statement of human and animal rights

Statement of informed consent

Author contributions

Funding

Declaration of conflicting interests

Data availability statement

References