Regulation Of Stem Cell Fate Research Articles

Human Pluripotent Stem Cell Fate Regulation by SMARCB1.

SummaryEpigenetic regulation by the SWI/SNF complex is essential for normal self-renewal capacity and pluripotency of human pluripotent stem cells (hPSCs). It has been shown that different subunits of the complex have a distinct role in this regulation. Specifically, the SMARCB1 subunit has been shown to regulate the activity of enhancers in diverse types of cells, including hPSCs. Here, we report the establishment of conditional hPSC lines, enabling control of SMARCB1 expression from complete loss of function to significant overexpression. Using this system, we show that any deviation from normal SMARCB1 expression leads to cell differentiation. We further found that SMARCB1 expression is not required for differentiation of hPSCs into progenitor cells, but rather for later stages of differentiation. Finally, we identify SMARCB1 as a critical player in regulation of cell-cell and cell-ECM interactions in hPSCs and show that this regulation is mediated at least in part by the WNT pathway.

Sensory nerves in the spotlight of the stem cell niche.

Niches are specialized tissue microenvironments that control stem cells functioning. The bone marrow mesenchymal stem cell niche defines a location within the marrow in which mesenchymal stem cells are retained and produce new cells throughout life. Deciphering the signaling mechanisms by which the niche regulates stem cell fate will facilitate the use of these cells for therapy. Recent studies, by using state‐of‐the‐art methodologies, including sophisticated in vivo inducible genetic techniques, such as lineage‐tracing Cre/loxP mediated systems, in combination with pharmacological inhibition, provide evidence that sensory neuron is an important component of the bone marrow mesenchymal stem cell niche. Strikingly, knockout of a specific receptor in sensory neurons blocked stem cell function in the bone marrow. The knowledge arising from these discoveries will be crucial for stem cell manipulation in the future. Here, we review recent progress in our understanding of sensory nerves biology in the stem cell niche.

Strontium regulates stem cell fate during osteogenic differentiation through asymmetric cell division

Strontium, a popular osteogenic component, has been incorporated into various types of orthopaedic biomaterials to enhance bone regeneration. Strontium performs dual effects in promoting bone formation and inhibiting bone resorption. Previous studies have focused on the effects of strontium ions (Sr2+) in regulating stem cell behavior to initiate regenerative capacity. However, its mechanisms for regulating the fate and homeostasis of stem cells have not been fully elucidated. In this study, the promotive effect of Sr2+ on the osteogenic differentiation of mesenchymal stem cells was confirmed both in vitro and in vivo. Interestingly, in response to Sr2+ treatment, stem cells performed asymmetric cell division to balance stemness maintenance and osteogenic differentiation. In initiating osteogenic differentiation, Sr2+ maintained more cells in the cell cycle by upregulating the population of S and G2/M phase cells, and this increase in the cell population contributed to enhanced osteogenic differentiation. The divided cells with different cell fates were observed, with one daughter cell maintained stemness, while the other committed to osteogenic lineage. Further investigation revealed that Sr2+ activated noncanonical Wnt signaling to regulate the expression and distribution of the Par complex, thus regulating cell division. As a result, the daughter cells committed to different cell fates due to the discriminately activation of osteogenic transcription factors caused by asymmetrically distributed Par3 and aPKC. The results of this study could facilitate the design of biomaterials for bone regeneration by providing a better understanding of cell fate determination regulated by strontium.

Epigenetic Regulation of Dental Pulp Stem Cell Fate.

Epigenetic regulation, mainly involving DNA methylation, histone modification, and noncoding RNAs, affects gene expression without modifying the primary DNA sequence and modulates cell fate. Mesenchymal stem cells derived from dental pulp, also called dental pulp stem cells (DPSCs), exhibit multipotent differentiation capacity and can promote various biological processes, including odontogenesis, osteogenesis, angiogenesis, myogenesis, and chondrogenesis. Over the past decades, increased attention has been attracted by the use of DPSCs in the field of regenerative medicine. According to a series of studies, epigenetic regulation is essential for DPSCs to differentiate into specialized cells. In this review, we summarize the mechanisms involved in the epigenetic regulation of the fate of DPSCs.

The landscape of GPCR signaling in the regulation of epidermal stem cell fate and skin homeostasis.

Continuous integration of signals from the micro and macro-environment is necessary for somatic stem cells to adapt to changing conditions, maintain tissue homeostasis and activate repair mechanisms. G-protein coupled receptors (GPCRs) facilitate this integration by binding to numerous hormones, metabolites and inflammatory mediators, influencing a diverse network of pathways that regulate stem cell fate. This adaptive mechanism is particularly relevant for tissues that are exposed to environmental assault, like skin. The skin is maintained by a set of basal keratinocyte stem and progenitor cells located in the hair follicle and interfollicular epidermis, and several GPCRs and their signaling partners serve as makers and regulators of epidermal stem cell activity. GPCRs utilize heterotrimeric G protein dependent and independent pathways to translate extracellular signals into intracellular molecular cascades that dictate the activation of keratinocyte proliferative and differentiation networks, including Hedgehog GLI, Hippo YAP1 and WNT/β-catenin, ultimately regulating stem cell identity. Dysregulation of GPCR signaling underlines numerous skin inflammatory diseases and cancer, with smoothened-driven basal cell carcinoma being a main example of a GPCR associated cancer. In this review, we discuss the impact of GPCRs and their signaling partners in skin keratinocyte biology, particularly in the regulation of the epidermal stem cell compartment.

Mesenchymal Stromal Cells as Critical Contributors to Tissue Regeneration.

Adult stem cells that are tightly regulated by the specific microenvironment, or the stem cell niche, function to maintain tissue homeostasis and regeneration after damage. This demands the existence of specific niche components that can preserve the stem cell pool in injured tissues and restore the microenvironment for their subsequent appropriate functioning. This role may belong to mesenchymal stromal cells (MSCs) due to their resistance to damage signals and potency to be specifically activated in response to tissue injury and promote regeneration by different mechanisms. Increased amount of data indicate that activated MSCs are able to produce factors such as extracellular matrix components, growth factors, extracellular vesicles and organelles, which transiently substitute the regulatory signals from missing niche cells and restrict the injury-induced responses of them. MSCs may recruit functional cells into a niche or differentiate into missing cell components to endow a niche with ability to regulate stem cell fates. They may also promote the dedifferentiation of committed cells to re-establish a pool of functional stem cells after injury. Accumulated evidence indicates the therapeutic promise of MSCs for stimulating tissue regeneration, but the benefits of administered MSCs demonstrated in many injury models are less than expected in clinical studies. This emphasizes the importance of considering the mechanisms of endogenous MSC functioning for the development of effective approaches to their pharmacological activation or mimicking their effects. To achieve this goal, we integrate the current ideas on the contribution of MSCs in restoring the stem cell niches after damage and thereby tissue regeneration.

Lipidomics of mesenchymal stem cell differentiation

Mesenchymal stem cells (MSCs), such as adipose-derived stem cells (ADSCs) and skeletal muscle-derived stem cells (MDSCs), are potential sources for cell-based therapeutic strategies. However, there is little knowledge about the lipid composition of these stem cells and the mechanisms of their differentiation. Lipids have important biological and physiological functions that are critical for understanding the regulation and control of stem cell fate. This study sought to analyze the lipidome of rabbit ADSCs and MDSCs and their adipogenic and osteogenic differentiation. The MSCs were isolated and were characterized by flow cytometry. Lipids were extracted from both MSCs and differentiated cells, and the lipids were subsequently analyzed with a hybrid triple quadrupole time-of-flight mass spectrometer. The results showed a total of 1687 lipid species. MSCs exhibited different lipid profiles as well as changes in lipid composition after differentiation. Furthermore, the expression levels of N-acyl-phosphatidylethanolamine (NAPE) 54:7+NH4 (-FA 17:0(NH4)) and phosphatidylcholine (PC) 42:6+Na were higher in the adipogenic lineages in of both MSC types, and NAPE 58:2+NH4 (-FA 17:0 (NH4)) and NAPE 56:2+NH4 (-FA 17:0 (NH4)) had higher levels in the osteogenic lineages, suggesting lipid similarities in cells differentiated from different stem cell sources.

Regulation of bone marrow mesenchymal stem cell fate by long non-coding RNA.

Bone mesenchymal stem cells (BMSCs) are progenitor cells isolated from bone marrow, which keep potential to differentiate into several kinds of cells including osteoblasts and adipocytes. A dynamic mutual regulation exists between osteogenesis and adipogenesis processes. Long non-coding RNA (lncRNA) performs diverse functions in biological activities including regulation of BMSCs commitment. Evidence has shown that lncRNA regulates key signaling pathways including TGFβ/BMP, Wnt and Notch pathways, and several transcription factors in BMSCs differention. Dysregulation of lncRNA in BMSCs leads to disruption of osteo-adipogenesis difffrentiation and results in impairment of bone homeostasis. In this review, we focus on the role of lncRNA in several critical signaling pathways that involved in regulation of osteo-adipogenesis of BMSC and prospects the potential clinical application of lncRNA.

Mechanically induced formation and maturation of 3D-matrix adhesions (3DMAs) in human mesenchymal stem cells

Mechanical signal is important for regulating stem cell fate, but the molecular mechanisms involved are unclear. Cell-matrix adhesions are important molecular mechanosensors that their formation and maturation are force-dependent processes. However, most studies focused on the role of cell contractility or substrate stiffness in these processes. How external mechanical force stimulates the formation and maturation of cell-matrix adhesions is largely unknown. Here, by using human mesenchymal stem cells (hMSCs)-collagen microtissues as a 3D model, we found that upon short-term dynamic compression, integrin αV binding, focal adhesion formation, and subsequent FAK activation, are stimulated. This compression-stimulated FAK signaling also leads to YAP activation, suggesting crosstalk between integrin-based signaling and mechanosensing. More importantly, long-term compression induces maturation of α5-integrin based adhesions to form long, slender 3D-matrix adhesions (3DMAs), which are distinct from 2D focal adhesions in composition and morphology and previously found only in cell-derived matrices and native tissues. Mechanical preconditioning hMSCs with long-term compression loading induces the formation of mature integrin α5-dependent 3DMAs and potentiates their osteogenesis. Collectively, this work shows that active mechanical stimulation can modulate cell-matrix interactions significantly at the cell-material interfaces in a dynamic manner, and affects cell fate decisions, demonstrating the significance of loading-based functional tissue engineering.

3020 – THE CLONAL AND MOLECULAR AETIOLOGY OF EMERGENCY DENDRITIC CELL DEVELOPMENT

Extrinsic regulation of single haematopoietic stem and progenitor cell (HSPC) fate is crucial for immune cell development. Here, we examine the aetiology of Flt3 ligand (Flt3L)-mediated emergency development of type 1 conventional dendritic cells (cDC1s), which results in enhanced immunity against infections and cancer. Using cellular barcoding, we demonstrate a predominant role of enhanced clonal expansion and moderate contribution via recruitment of additional cDC1-generating HSPCs. The selective cDC1 expansion occurs primarily via multi-/oligo-potent clones, without compromising output to other lineages. To understand the molecular hallmarks early during a Flt3L response, we develop Divi-Seq to simultaneously profile cell division history, surface phenotype and transcriptional state of single HSPCs. We discover that Flt3L-responsive HSPCs maintain a proliferative ‘early progenitor'-like state, which leads to selective emergence of CD11c+cKit+ transitional precursors with high cellular output to cDC1s. These findings inform the mechanistic action of Flt3L in natural immunity and immunotherapy at a clonal level.

Strontium Regulates Stem Cells Fates During Osteogenic Differentiation Through an Asymmetric Cell Division

Strontium as a popular osteogenic component has been incorporated into various types of orthopaedic biomaterials to enhance bone regeneration. It performs dual effects in promoting bone formation and inhibiting bone resorption. Studies have focused on the effects of strontium in regulating stem cells behaviors to initiate regenerative capacity. However, the mechanism of strontium on regulating stem cells fates and homeostasis has not been fully elucidated. In this study, the promoted effect of strontium on osteogenic differentiation of mesenchymal stem cells was confirmed both in vitro and in vivo. Interestingly, in responding to strontium treatment, stem cells performed asymmetric cell division to balance stemness maintenance and osteogenic differentiation. Asymmetric distribution of Par complex in daughter stem cells induced different cell fates by discriminately activating of osteogenic transcription factors. Strontium activated noncanonical Wnt signaling to regulate Par complex distribution. Understanding the mechanism of strontium on regulating stem cell fate could facilitate biomaterials designing to initiate endogenous bone regenerative capacity.

Organelle Cooperation in Stem Cell Fate: Lysosomes as Emerging Regulators of Cell Identity.

Regulation of stem cell fate is best understood at the level of gene and protein regulatory networks, though it is now clear that multiple cellular organelles also have critical impacts. A growing appreciation for the functional interconnectedness of organelles suggests that an orchestration of integrated biological networks functions to drive stem cell fate decisions and regulate metabolism. Metabolic signaling itself has emerged as an integral regulator of cell fate including the determination of identity, activation state, survival, and differentiation potential of many developmental, adult, disease, and cancer-associated stem cell populations and their progeny. As the primary adenosine triphosphate-generating organelles, mitochondria are well-known regulators of stem cell fate decisions, yet it is now becoming apparent that additional organelles such as the lysosome are important players in mediating these dynamic decisions. In this review, we will focus on the emerging role of organelles, in particular lysosomes, in the reprogramming of both metabolic networks and stem cell fate decisions, especially those that impact the determination of cell identity. We will discuss the inter-organelle interactions, cell signaling pathways, and transcriptional regulatory mechanisms with which lysosomes engage and how these activities impact metabolic signaling. We will further review recent data that position lysosomes as critical regulators of cell identity determination programs and discuss the known or putative biological mechanisms. Finally, we will briefly highlight the potential impact of elucidating mechanisms by which lysosomes regulate stem cell identity on our understanding of disease pathogenesis, as well as the development of refined regenerative medicine, biomarker, and therapeutic strategies.

Regulation of Hematopoietic Stem Cell Fate and Malignancy.

The regulation of hematopoietic stem cell (HSC) fate decision, whether they keep quiescence, self-renew, or differentiate into blood lineage cells, is critical for maintaining the immune system throughout one’s lifetime. As HSCs are exposed to age-related stress, they gradually lose their self-renewal and regenerative capacity. Recently, many reports have implicated signaling pathways in the regulation of HSC fate determination and malignancies under aging stress or pathophysiological conditions. In this review, we focus on the current understanding of signaling pathways that regulate HSC fate including quiescence, self-renewal, and differentiation during aging, and additionally introduce pharmacological approaches to rescue defects of HSC fate determination or hematopoietic malignancies by kinase signaling pathways.

Fatty acid β-oxidation is required for the differentiation of larval hematopoietic progenitors in Drosophila.

Cell-intrinsic and extrinsic signals regulate the state and fate of stem and progenitor cells. Recent advances in metabolomics illustrate that various metabolic pathways are also important in regulating stem cell fate. However, our understanding of the metabolic control of the state and fate of progenitor cells is in its infancy. Using Drosophila hematopoietic organ: lymph gland, we demonstrate that Fatty Acid Oxidation (FAO) is essential for the differentiation of blood cell progenitors. In the absence of FAO, the progenitors are unable to differentiate and exhibit altered histone acetylation. Interestingly, acetate supplementation rescues both histone acetylation and the differentiation defects. We further show that the CPT1/whd (withered), the rate-limiting enzyme of FAO, is transcriptionally regulated by Jun-Kinase (JNK), which has been previously implicated in progenitor differentiation. Our study thus reveals how the cellular signaling machinery integrates with the metabolic cue to facilitate the differentiation program.

Composition and Mechanism of Three-Dimensional Hydrogel System in Regulating Stem Cell Fate.

Three-dimensional (3D) hydrogel systems integrating different types of stem cells and scaffolding biomaterials have an important application in tissue engineering. The biomimetic hydrogels that pattern cell suspensions within 3D configurations of biomaterial networks allow for the transport of bioactive factors and mimic the stem cell niche in vivo, thereby supporting the proliferation and differentiation of stem cells. The composition of a 3D hydrogel system determines the physical and chemical characteristics that regulate stem cell function through a biological mechanism. Here, we discuss the natural and synthetic hydrogel compositions that have been employed in 3D scaffolding, focusing on their characteristics, fabrication, biocompatibility, and regulatory effects on stem cell proliferation and differentiation. We also discuss the regulatory mechanisms of cell-matrix interaction and cell-cell interaction in stem cell activities in various types of 3D hydrogel systems. Understanding hydrogel compositions and their cellular mechanisms can yield insights into how scaffolding biomaterials and stem cells interact and can lead to the development of novel hydrogel systems of stem cells in tissue engineering and stem cell-based regenerative medicine. Impact statement Three-dimensional hydrogel system of stem cell mimicking the stemcell niche holds significant promise in tissue engineering and regenerative medicine. Exactly how hydrogel composition regulates stem cell fate is not well understood. This review focuses on the composition of hydrogel, and how the hydrogel composition and its properties regulate the stem cell adhesion, growth, and differentiation. We propose that cell-matrix interaction and cell-cell interaction are important regulatory mechanisms in stem cell activities. Our review provides key insights into how the hydrogel composition regulates the stem cell fate, untangling the engineering of three-dimensional hydrogel systems for stem cells.

SAT-284 Musashi Exerts Translational Control Within Anterior Pituitary Cells of the POU1F1 Lineage

The activation of transcription factor Pou1f1 at embryonic day 13 gives rise to the pituitary populations of somatotropes, lactotropes, and thyrotropes and these populations maintain expression of Pou1f1 throughout life. The Musashi family of RNA regulatory proteins is known to regulate stem cell fate by repressing translation of target mRNAs needed for differentiation. Previously our lab has shown that female Lepr-null somatotropes have reduced POU1F1 protein levels but do not have changes in Pou1f1 mRNA expression. Stimulation with leptin increased the POU1F1 protein levels 3-fold, but did not change Pou1f1 mRNA suggesting a post-transcriptional mechanism for leptin’s regulation of Pou1f1. An in silico analysis indicated the presence a number of potential regulatory elements (MBEs) within the Pou1f1 mRNA 3’ UTR, including 8 consensus Musashi binding elements. Interestingly, we found musashi mRNA and protein levels were increased in Lepr-null somatotropes. This suggested that leptin regulates the expression of musashi in somatotrope populations and may be a candidate translational regulator of the Pou1f1 mRNA. We verified that MSI binds directly to the Pou1f1 mRNA 3’ UTR MBEs by EMSA in vitro and exerts translational repression (using reporter mRNA assays in transfected cell populations). Single cell RNA sequencing of pituitary cells from control male and female mice indicates that MSI and Pou1f1 mRNAs are co-expressed in somatotropes, lactotropes as well as thyrotropes. Immunocytochemical analyses confirmed that Musashi protein is present in mixed and purified somatotrope populations. Furthermore, immunoprecipitation with Musashi1 antibody showed a 5-fold enrichment of Pou1f1 mRNA in control female mouse pituitaries. These findings point to a critical in vivo role for Musashi-mediated mRNA translational regulation within the Pou1f1 lineage and specifically in the control of somatotrope maturation and response to metabolic cues.

Engineering Stem Cell-Derived Extracellular Matrices: Decellularization, Characterization, and Biological Function.

Stem cells, including mesenchymal stem cells and pluripotent stem cells, have attracted considerable attention in tissue engineering and regenerative medicine primarily because of their unique ability in self-renewal and multilineage differentiation. However, stem cells also have important secretory functions that form a specialized in vivo microenvironment and direct tissue development and regeneration. Extracellular matrices (ECMs) derived from stem cells retain the functional properties of their native environment and exhibit unique signaling that mediates stem cell self-renewal and lineage commitment. Stem cell-derived ECMs (scECMs) also have tunable properties corresponding to their developmental stages, suggesting that their lineage- and developmental specificity can be engineered for a wide range of applications. Hence, there is a growing interest in reconstructing stem cell microenvironment through decellularization and obtaining decellularized matrices that exhibit unique biological properties. This article summarizes recent advances in the use and understanding of scECMs. Moreover, future directions to extend the spectrum of applications of stem-derived ECMs in tissue engineering by comprehensively elucidating and engineering their regulatory function is highlighted. Impact statement Stem cells bear unique potency for multilineage differentiation as well as the capacity to secrete a vast amount of regulatory molecules. At different developmental stages, the extracellular matrices (ECMs) secreted by stem cells regulate their microenvironment and direct tissue development. The decellularization of stem cells effectively preserves ECM functional properties and can provide suitable templates to regulate stem cell fate decision, which can hardly be reproduced using single ECM proteins or synthetic scaffolds. This review highlights the unique regulatory functions of stem cell-derived ECMs, which can serve as novel sources of highly bioactive materials for tissue engineering and cell therapy.

Metabolic Regulation of Stem Cell Fate and Function

The overarching goal of this project is to understand how diet‐derived nutrients regulate stem cell metabolism and downstream fate decisions in the setting of normal development and disease. Quiescent adult stem cells typically favor glycolytic metabolism over the oxidative metabolism utilized by differentiating cells. Importantly, manipulating stem cell metabolism is sufficient to alter cell fate decisions. While the serum concentrations of endogenous metabolites such as glucose and lactate are under homeostatic constraints, diet can cause vast fluctuations in circulating levels of certain metabolites that serve as co‐factors for chromatin and DNA modifying enzymes. As such, exogenous nutrients can control the epigenome and gene expression programs, thus altering differentiation and cell fate. However, little is known about how changing nutrient levels will affect the metabolism and chromatin status in the adult stem cell populations. To address this question, we have adapted a recently described mouse liver organoid system. The liver coordinates whole‐body metabolism and detoxification, and therefore is acutely tuned to respond to dietary changes. Liver organoids generate 3D assemblies that mirror the native physiology of the tissue and self‐renew in vitro due to the activity of Wnt‐responsive stem cells that reside in the hepatic ductal compartment. We have found that treatment with physiologically attainable concentrations of ascorbic acid inhibits hepatic organoid expansion in a dose‐dependent manner. Ascorbic acid, commonly known as Vitamin C, is a water‐soluble antioxidant that is obtained exclusively through the diet in humans. Ascorbic acid is an essential co‐factor for the Fe‐ and α‐ketoglutarate dependent dioxygenase (α‐KGDDs) class of enzymes, which includes collagen hydroxylases, prolyl hydroxylases, and epigenetic erasers such as DNA and histone demethylases. To determine if activation of α‐KGDDs enzymes suppresses organoid expansion, we treated hepatic organoids with a cell permeable form of α‐KG and observed growth inhibition identical to that observed with ascorbic acid treatment. α‐KG/succinate ratios and expression of the ascorbate transporters increases in differentiated hepatic organoids compared to cultures maintained in expansion media, suggesting that ascorbic acid may preferentially accumulate and function during terminal differentiation. Taken together, we propose that ascorbic acid acts as a cofactor for α‐KGDD enzymes in order to restrain stem cell activity and may play a role in promoting differentiation to the hepatic lineage.Support or Funding InformationS.N.S is supported by a postdoctoral grant from the Eli and Edythe Broad Stem Cell Research Center at UCLA. H.R.C is supported by a CTSI seed grant from the David Geffen School of Medicine at UCLA.

Asymmetric assembly of centromeres epigenetically regulates stem cell fate.

Centromeres are epigenetically defined by CENP-A-containing chromatin and are essential for cell division. Previous studies suggest asymmetric inheritance of centromeric proteins upon stem cell division; however, the mechanism and implications of selective chromosome segregation remain unexplored. We show that Drosophila female germline stem cells (GSCs) and neuroblasts assemble centromeres after replication and before segregation. Specifically, CENP-A deposition is promoted by CYCLIN A, while excessive CENP-A deposition is prevented by CYCLIN B, through the HASPIN kinase. Furthermore, chromosomes inherited by GSCs incorporate more CENP-A, making stronger kinetochores that capture more spindle microtubules and bias segregation. Importantly, symmetric incorporation of CENP-A on sister chromatids via HASPIN knockdown or overexpression of CENP-A, either alone or together with its assembly factor CAL1, drives stem cell self-renewal. Finally, continued CENP-A assembly in differentiated cells is nonessential for egg development. Our work shows that centromere assembly epigenetically drives GSC maintenance and occurs before oocyte meiosis.

Dietary phytochemical approaches to stem cell regulation

Controlling proliferation and lineage differentiation of stem cells is critical for stem cell therapy in regenerative medicine. Phytochemicals such as phenols, flavonoids, sterols and alkaloids chemicals derived from food or herbs have obvious effects on modulating the self-renewal and function of stem cells, which are promising for the cooperative application with stem cells in various diseases. • Regulating stem cell fate is critical for regenerative medicine. • Dietary phytochemicals modulate stem-cell fate via multiple signal pathways. • Phytochemicals are promising for stem cell-based therapies. Controlling self-renewal and lineage differentiation of stem cells (SCs) is critical for SC therapy in regenerative medicine. Multiple signal pathways such as Wnt, TGF-β and BMP are involved in modulating proliferation or specific differentiation of different types of SCs. Dietary phytochemicals, the major source of new drugs, are found to stimulate self-renewal and sub-population differentiation of SCs by activating/inhibiting the signal pathways (MAPK, canonical Wnt/β-catenin, AKT, etc.) and key transcription factors (OCT4, NANOG, Runx2, etc.). Dietary phytochemicals are important for SC therapy owing to the plethora of targets. In this review, we discussed the SC types and their regulatory mechanism. Applications of phenols, flavonoids, sterols and alkaloids chemicals from food or herbs on targeting SCs along with their molecular mechanisms are also discussed. Dietary phytochemicals are promising to enhance endogenous/exogenous SC therapy in various diseases.