Maintenance Of Stem Cell Niche Research Articles

Cytological Effects of Cadmium Poisoning and the Protective Effect of Quercetin: A Mechanism Exploration based on the Testicular Lamina Propria.

This comprehensive study delved into the detrimental effects of cadmium (Cd), a toxic heavy metal, on the testicular lamina propria (LP), a key player in spermatogenesis, and the maintenance of testicular stem cell niches. Utilizing transmission electron microscopy, immunohistochemistry, and double-labeling immunofluorescence, the research characterized the structural and cellular components of mouse testicular LP under Cd exposure and investigated the protective effects of quercetin. The findings illustrated that Cd exposure results in significant morphological and cellular modifications within the LP, including the apoptosis of peritubular myoid cells, an upsurge in CD34+ stromal cells displaying anti-apoptotic behaviors, and an excessive production of collagen Type I fibers and extracellular matrix. Remarkably, quercetin effectively counteracted these adverse changes by reversing apoptosis, reducing the proliferation of CD34+ stromal cells, and addressing fibrosis markers, thereby mitigating the cellular damage induced by Cd. This study not only highlighted the critical impact of apoptosis and fibrosis in Cd-related testicular damage but also elucidated the protective mechanism of quercetin, laying the groundwork for future clinical applications in addressing testicular damage from heavy metal poisoning through cellular therapeutics and pharmacological interventions.

Roles of Histone Acetylation and Deacetylation in Root Development

Roots are usually underground plant organs, responsible for anchoring to the soil, absorbing water and nutrients, and interacting with the rhizosphere. During root development, roots respond to a variety of environmental signals, contributing to plant survival. Histone post-translational modifications play essential roles in gene expression regulation, contributing to plant responses to environmental cues. Histone acetylation is one of the most studied post-translational modifications, regulating numerous genes involved in various biological processes, including development and stress responses. Although the effect of histone acetylation on plant responses to biotic and abiotic stimuli has been extensively reviewed, no recent reviews exist focusing on root development regulation by histone acetylation. Therefore, this review brings together all the knowledge about the impact of histone acetylation on root development in several plant species, mainly focusing on Arabidopsis thaliana. Here, we summarize the role of histone acetylation and deacetylation in numerous aspects of root development, such as stem cell niche maintenance, cell division, expansion and differentiation, and developmental zone determination. We also emphasize the gaps in current knowledge and propose new perspectives for research toward deeply understanding the role of histone acetylation in root development.

The Conundrum of Mechanics Versus Genetics in Congenital Hydrocephalus and Its Implications for Fetal Therapy Approaches: A Scoping Review.

Recent advances in gene therapy, particularly for single-gene disorders (SGDs), have led to significant progress in developing innovative precision medicine approaches that hold promise for treating conditions such as primary hydrocephalus (CH), which is characterized by increased cerebrospinal fluid (CSF) volumes and cerebral ventricular dilation as a result of impaired brain development, often due to genetic causes. CH is a significant contributor to childhood morbidity and mortality and a driver of healthcare costs. In many cases, prenatal ultrasound can readily identify ventriculomegaly as early as 14-20weeks of gestation, with severe cases showing poor neurodevelopmental outcomes. Postnatal surgical approaches, such as ventriculoperitoneal shunts, do not address the underlying genetic causes, have high complication rates, and result in a marginal improvement of neurocognitive deficits. Prenatal somatic cell gene therapy (PSCGT) promises a novel approach to conditions such as CH by targeting genetic mutations in utero, potentially improving long-term outcomes. To better understand the pathophysiology, genetic basis, and molecular pathomechanisms of CH, we conducted a scoping review of the literature that identified over 160 published genes linked to CH. Mutations in L1CAM, TRIM71, MPDZ, and CCDC88C play a critical role in neural stem cell development, subventricular zone architecture, and the maintenance of the neural stem cell niche, driving the development of CH. Early prenatal interventions targeting these genes could curb the development of the expected CH phenotype, improve neurodevelopmental outcomes, and possibly limit the need for surgical approaches. However, further research is needed to establish robust genotype-phenotype correlations and develop safe and effective PSCGT strategies for CH.

ATP Hydrolases Superfamily Protein 1 (ASP1) Maintains Root Stem Cell Niche Identity through Regulating Reactive Oxygen Species Signaling in Arabidopsis.

The maintenance of the root stem cell niche identity in Arabidopsis relies on the delicate balance of reactive oxygen species (ROS) levels in root tips; however, the intricate molecular mechanisms governing ROS homeostasis within the root stem cell niche remain unclear. In this study, we unveil the role of ATP hydrolase superfamily protein 1 (ASP1) in orchestrating root stem cell niche maintenance through its interaction with the redox regulator cystathionine β-synthase domain-containing protein 3 (CBSX3). ASP1 is exclusively expressed in the quiescent center (QC) cells and governs the integrity of the root stem cell niche. Loss of ASP1 function leads to enhanced QC cell division and distal stem cell differentiation, attributable to reduced ROS levels and diminished expression of SCARECROW and SHORT ROOT in root tips. Our findings illuminate the pivotal role of ASP1 in regulating ROS signaling to maintain root stem cell niche homeostasis, achieved through direct interaction with CBSX3.

Hematopoietic stem cell niche generation and maintenance are distinguishable by an epitranscriptomic program

The niche is typically considered as a pre-established structure sustaining stem cells. Therefore, the regulation of its formation remains largely unexplored. Whether distinct molecular mechanisms control the establishment versus maintenance of a stem cell niche is unknown. To address this, we compared perinatal and adult bone marrow mesenchymal stromal cells (MSCs), a key component of the hematopoietic stem cell (HSC) niche. MSCs exhibited enrichment in genes mediating m6A mRNA methylation at the perinatal stage and downregulated the expression of Mettl3, the m6A methyltransferase, shortly after birth. Deletion of Mettl3 from developing MSCs but not osteoblasts led to excessive osteogenic differentiation and a severe HSC niche formation defect, which was significantly rescued by deletion of Klf2, an m6A target. In contrast, deletion of Mettl3 from MSCs postnatally did not affect HSC niche. Stem cell niche generation and maintenance thus depend on divergent molecular mechanisms, which may be exploited for regenerative medicine.

Cadherin-dependent adhesion is required for muscle stem cell niche anchorage and maintenance.

Adhesion between stem cells and their niche provides stable anchorage and signaling cues to sustain properties such as quiescence. Skeletal muscle stem cells (MuSCs) adhere to an adjacent myofiber via cadherin-catenin complexes. Previous studies on N- and M-cadherin in MuSCs revealed that although N-cadherin is required for quiescence, they are collectively dispensable for MuSC niche localization and regenerative activity. Although additional cadherins are expressed at low levels, these findings raise the possibility that cadherins are unnecessary for MuSC anchorage to the niche. To address this question, we conditionally removed from MuSCs β- and γ-catenin, and, separately, αE- and αT-catenin, factors that are essential for cadherin-dependent adhesion. Catenin-deficient MuSCs break quiescence similarly to N-/M-cadherin-deficient MuSCs, but exit the niche and are depleted. Combined in vivo, ex vivo and single cell RNA-sequencing approaches reveal that MuSC attrition occurs via precocious differentiation, re-entry to the niche and fusion to myofibers. These findings indicate that cadherin-catenin-dependent adhesion is required for anchorage of MuSCs to their niche and for preservation of the stem cell compartment. Furthermore, separable cadherin-regulated functions govern niche localization, quiescence and MuSC maintenance.

PHYTOCHROME A controls the DNA damage response and cell death tolerance within the Arabidopsis root meristem.

The DNA damage response avoids mutations into dividing cells. Here, we analysed the role of photoreceptors on the restriction of root growth imposed by genotoxic agents and its relationship with cell viability and performance of meristems. Comparison of root growth of Arabidopsis WT, phyA-211, phyB-9, and phyA-211phyB-9 double mutants unveiled a critical role for phytochrome A (PhyA) in protecting roots from genotoxic stress, regeneration and cell replenishment in the meristematic zone. PhyA was located on primary root tips, where it influences genes related to the repair of DNA, including ERF115 and RAD51. Interestingly, phyA-211 mutants treated with zeocin failed to induce the expression of the repressor of cell cycle MYB3R3, which correlated with expression of the mitotic cyclin CycB1, suggesting that PhyA is required for safeguarding the DNA integrity during cell division. Moreover, the growth of the primary roots of PhyA downstream component HY5 and root growth analyses in darkness suggest that cell viability and DNA damage responses within root meristems may act independently from light and photomorphogenesis. These data support novel roles for PhyA as a key player for stem cell niche maintenance and DNA damage responses, which are critical for proper root growth.

ULTRAPETALAs in action: Unraveling their role in root development

The epigenetic complex Trithorax (TrxG) regulates gene transcription through post-translational histone modifications and is involved in a wide range of developmental processes. ULTRAPETALA1 (ULT1) is a SAND domain plant-exclusive TrxG protein that regulates the H3K4me3 active mark to counteract PcG repression. ULT1 has been identified to be involved in multiple tissue-specific processes. In the Arabidopsis root, ULT1 is required to maintain the stem cell niche, a role that is independent of the histone methyltransferase ATX1. Here we show the contribution of ULT2 in the maintenance of root stem cell niche. We also analyzed the gene expression in the ult1, ult2, and ult1ult2 mutants, evidencing three ways in which ULT1 and ULT2 regulate gene expression, one of them, where ULT1 or ULT2 regulate specific genes each, another where ULT1 and ULT2 act redundantly, as well as a regulation that requires of ULT1 and ULT2 together, supporting a coregulation, never reported. Furthermore, we also evidenced the participation of ULT1 in transcriptional repression synergically with CLF, a key histone methyltransferase of PcG.

Maintenance of stem cell activity in plant development and stress responses.

Stem cells residing in plant apical meristems play an important role during postembryonic development. These stem cells are the wellspring from which tissues and organs of the plant emerge. The shoot apical meristem (SAM) governs the aboveground portions of a plant, while the root apical meristem (RAM) orchestrates the subterranean root system. In their sessile existence, plants are inextricably bound to their environment and must adapt to various abiotic stresses, including osmotic stress, drought, temperature fluctuations, salinity, ultraviolet radiation, and exposure to heavy metal ions. These environmental challenges exert profound effects on stem cells, potentially causing severe DNA damage and disrupting the equilibrium of reactive oxygen species (ROS) and Ca2+ signaling in these vital cells, jeopardizing their integrity and survival. In response to these challenges, plants have evolved mechanisms to ensure the preservation, restoration, and adaptation of the meristematic stem cell niche. This enduring response allows plants to thrive in their habitats over extended periods. Here, we presented a comprehensive overview of the cellular and molecular intricacies surrounding the initiation and maintenance of the meristematic stem cell niche. We also delved into the mechanisms employed by stem cells to withstand and respond to abiotic stressors.

Autophagy drives the conversion of developmental neural stem cells to the adult quiescent state

Neurogenesis in the adult mammalian brain relies on the lifelong persistence of quiescent neural stem cell (NSC) reservoirs. Little is known about the mechanisms that lead to the initial establishment of quiescence, the main hallmark of adult stem cells, during development. Here we show that protein aggregates and autophagy machinery components accumulate in developmental radial glia-like NSCs as they enter quiescence and that pharmacological or genetic blockade of autophagy disrupts quiescence acquisition and maintenance. Conversely, increasing autophagy through AMPK/ULK1 activation instructs the acquisition of the quiescent state without affecting BMP signaling, a gatekeeper of NSC quiescence during adulthood. Selective ablation of Atg7, a critical gene for autophagosome formation, in radial glia-like NSCs at early and late postnatal stages compromises the initial acquisition and maintenance of quiescence during the formation of the hippocampal dentate gyrus NSC niche. Therefore, we demonstrate that autophagy is cell-intrinsically required to establish NSC quiescence during hippocampal development. Our results uncover an important role of autophagy in the transition of developmental NSCs into their dormant adult form, paving the way for studies directed at further understanding the mechanisms of stem cell niche formation and maintenance in the mammalian brain.

Functional Pdgfra fibroblast heterogeneity in normal and fibrotic mouse lung.

Aberrant fibroblast function plays a key role in the pathogenesis of idiopathic pulmonary fibrosis, a devastating disease of unrelenting extracellular matrix deposition in response to lung injury. Platelet-derived growth factor α-positive (Pdgfra+) lipofibroblasts (LipoFBs) are essential for lung injury response and maintenance of a functional alveolar stem cell niche. Little is known about the effects of lung injury on LipoFB function. Here, we used single-cell RNA-Seq (scRNA-Seq) technology and PdgfraGFP lineage tracing to generate a transcriptomic profile of Pdgfra+ fibroblasts in normal and injured mouse lungs 14 days after bleomycin exposure, generating 11 unique transcriptomic clusters that segregated according to treatment. While normal and injured LipoFBs shared a common gene signature, injured LipoFBs acquired fibrogenic pathway activity with an attenuation of lipogenic pathways. In a 3D organoid model, injured Pdgfra+ fibroblast-supported organoids were morphologically distinct from those cultured with normal fibroblasts, and scRNA-Seq analysis suggested distinct transcriptomic changes in alveolar epithelia supported by injured Pdgfra+ fibroblasts. In summary, while LipoFBs in injured lung have not migrated from their niche and retain their lipogenic identity, they acquire a potentially reversible fibrogenic profile, which may alter the kinetics of epithelial regeneration and potentially contribute to dysregulated repair, leading to fibrosis.

Constructing epidermal rete ridges using a composite hydrogel to enhance multiple signaling pathways for the maintenance of epidermal stem cell niche.

The undulating microstructure rete ridge (RR) located at the junction between the dermis and epidermis plays a crucial role in improving skin mechanical properties and maintaining skin homeostasis. However, the investigation of RR microstructures is usually neglected in current tissue engineering for skin regeneration. Here, to create an epidermal model with RR microstructures, keratinocytes were cultured on a patterned GelMA-PEGDA hydrogel constructed using molding technology. Furthermore, grafting acryloylated Arg-Gly-Asp (RGD) peptides on the hydrogel surface significantly improved cell adhesion, fusion, and development. RT-PCR, Western blot, and immunofluorescence staining confirmed that cells on RR microstructures exhibited higher gene and protein expression associated with epidermal stem cells. RNA sequencing analysis of cells on RR microstructure showed higher gene expression profiles related to stem cell maintenance, basement membrane formation, and epidermal development. Furthermore, RT-PCR analysis of epidermal models of various dimensions demonstrated that smaller microstructures were more conducive to epidermal stem cell marker gene expression, which is analogous to human skin. Overall, we have successfully developed a method for integrating RR microstructures into an epidermal model that mimics natural skin to maintain epidermal stem cell niche, providing a valuable reference for researching skin regeneration within the fields of tissue engineering and regenerative medicine. STATEMENT OF SIGNIFICANCE: This study presents a method for precisely fabricating microstructures of skin rete ridges using composite hydrogels, thereby creating a skin model that mimics natural human skin. The findings reveal that this microstructure provides a stem cell niche that regulates the pathways and promotes the expression of proteins related to epidermal stem cells. This work advances the functional properties of tissue engineered skin and holds promise for improving the therapeutic efficacy of artificial skin grafts for the skin wounds.

Cytotoxic CD4 T cells in the mucosa and in cancer.

CD4 T cells were initially described as helper cells that promote either the cellular immune response (Th1 cells) or the humoral immune response (Th2 cells). Since then, a plethora of functionally distinct helper and regulatory CD4 T cell subsets have been described. CD4 T cells with cytotoxic function were first described in the setting of viral infections and autoimmunity, and more recently in cancer and gut dysbiosis. Regulatory CD4 T cell subsets such as Tregs and T-regulatory type 1 (Tr1) cells have also been shown to have cytotoxic potential. Indeed, Tr1 cells have been shown to be important for maintenance of stem cell niches in the bone marrow and the gut. This review will provide an overview of cytotoxic CD4 T cell development, and discuss the role of inflammatory and Tr1-like cytotoxic CD4 T cells in maintenance of intestinal stem cells and in anti-cancer immune responses.

Efficient Isolation and Expansion of Limbal Melanocytes for Tissue Engineering.

Limbal melanocytes (LMs) are found in the corneoscleral limbus basal epithelial layer and interact with neighboring limbal epithelial progenitor cells. The difficulty of isolating and cultivating LMs is due to the small fraction of LMs in the overall limbal population and the frequent contamination of primary cultures by other cell types. This has limited the research on freshly isolated LMs and the investigation of their biological significance in the maintenance of the limbal stem cell niche. Here, we describe an optimized protocol for the efficient isolation and expansion of LMs from cadaveric corneal limbal tissue using CD90 and CD117 as selective markers in fluorescence-activated cell sorting to obtain a pure population of LMs (CD90- CD117+) with self-renewal capacity and sustained melanin production. The isolation of pure LMs from a single preparation enables direct transcriptomic and proteomic analyses, as well as functional studies on freshly isolated LMs, which can be considered the proper counterparts of LMs in vivo and have potential applications in tissue engineering.

(Don't) Look Up!: Is short-root just a short-root plant?

SHORT-ROOT (SHR) is a mobile transcription factor that plays important roles in ground tissue patterning, stem cell niche specification and maintenance, and vascular development in Arabidopsis roots. Although mRNA and protein of SHR are also found in hypocotyls, inflorescence stems, and leaves, its role in the above-ground organs has been less explored. In most developmental cases, SHR, together with its partner SCARECROW (SCR), regulates the expression of downstream target genes in controlling formative and proliferative cell divisions. Accumulating evidence on the regulatory role of SHR in shoots suggests that SHR may also play key roles in the above-ground organs. Interestingly, recent work has provided new evidence that SHR is also required for cell elongation in the hypocotyl of the etiolated seedling. This suggests that the novel roles of SHR and SHR-mediated regulatory networks can be found in shoots. Furthermore, comparative research on SHR function in roots and shoots will broaden and deepen our understanding of plant growth and development.

Fabrication of initial trabecular bone-inspired three-dimensional structure with cell membrane nano fragments.

The extracellular matrix of trabecular bone has a large surface exposed to the bone marrow and plays important roles such as hematopoietic stem cell niche formation and maintenance. In vitro reproduction of trabecular bone microenvironment would be valuable not only for developing a functional scaffold for bone marrow tissue engineering but also for understanding its biological functions. Herein, we analyzed and reproduced the initial stages of trabecular bone formation in mouse femur epiphysis. We identified that the trabecular bone formation progressed through the following steps: (i) partial rupture of hypertrophic chondrocytes; (ii) calcospherite formation on cell membrane nano fragments (CNFs) derived from the ruptured cells; and (iii) calcospherite growth and fusion to form the initial three-dimensional (3D) structure of trabecular bones. For reproducing the initial trabecular bone formation in vitro, we collected CNFs from cultured cells and used as nucleation sites for biomimetic calcospherite formation. Strikingly, almost the same 3D structure of the initial trabecular bone could be obtained in vitro by using additional CNFs as a binder to fuse biomimetic calcospherites.

Fumonisin B1 as a Tool to Explore Sphingolipid Roles in Arabidopsis Primary Root Development.

Fumonisin B1 is a mycotoxin that is structurally analogous to sphinganine and sphingosine and inhibits the biosynthesis of complex sphingolipids by repressing ceramide synthase. Based on the connection between FB1 and sphingolipid metabolism, FB1 has been widely used as a tool to explore the multiple functions of sphingolipids in mammalian and plant cells. The aim of this work was to determine the effect of sphingolipids on primary root development by exposing Arabidopsis (Arabidopsis thaliana) seedlings to FB1. We show that FB1 decreases the expression levels of several PIN-FORMED (PIN) genes and the key stem cell niche (SCN)-defining transcription factor genes WUSCHEL-LIKE HOMEOBOX5 (WOX5) and PLETHORAs (PLTs), resulting in the loss of quiescent center (QC) identity and SCN maintenance, as well as stunted root growth. In addition, FB1 induces cell death at the root apical meristem in a non-cell-type-specific manner. We propose that sphingolipids play a key role in primary root growth through the maintenance of the root SCN and the amelioration of cell death in Arabidopsis.

P-Cadherin Is Expressed by Epithelial Progenitor Cells and Melanocytes in the Human Corneal Limbus.

Interactions between limbal epithelial progenitor cells (LEPC) and surrounding niche cells, which include limbal mesenchymal stromal cells (LMSC) and melanocytes (LM), are essential for the maintenance of the limbal stem cell niche required for a transparent corneal surface. P-cadherin (P-cad) is a critical stem cell niche adhesion molecule at various epithelial stem cell niches; however, conflicting observations were reported on the presence of P-cad in the limbal region. To explore this issue, we assessed the location and phenotype of P-cad+ cells by confocal microscopy of human corneoscleral tissue. In subsequent fluorescence-activated cell sorting (FACS) experiments, we used antibodies against P-cad along with CD90 and CD117 for the enrichment of LEPC, LMSC and LM, respectively. The sorted cells were characterized by immunophenotyping and the repopulation of decellularized limbal scaffolds was evaluated. Our findings demonstrate that P-cad is expressed by epithelial progenitor cells as well as melanocytes in the human limbal epithelial stem cell niche. The modified flow sorting addressing P-cad as well as CD90 and CD117 yielded enriched LEPC (CD90−CD117−P-cad+) and pure populations of LMSC (CD90+CD117−P-cad−) and LM (CD90−CD117+P-cad+). The enriched LEPC showed the expression of epithelial progenitor markers and better colony-forming ability than their P-cad− counterparts. The cultured LEPC and LM exhibited P-cad expression at intercellular junctions and successfully repopulated decellularized limbal scaffolds. These data suggest that P-cad is a critical cell–cell adhesion molecule, connecting LEPC and LM, which may play an important role in the long-term maintenance of LEPC at the limbal stem cell niche; moreover, these findings led to further improvement of cell enrichment protocols to enhance the yield of LEPC.

The miR‐200family regulates the epithelial stem cell niche during craniofacial and dental development

Introduction & objective‐The murine lower incisor ectodermal organ contains a single epithelial stem cell niche that provides epithelial progenitor cells to the continuously growing rodent incisor. Calvaria sutures also contain stem cells that are regulated by specific factors. We have discovered that the microRNA (miR) ‐200 family is required for stem cell differentiation through targeting stem cell factors. We asked if the miR‐200 family regulated specific stem cell niches during development.Materials & methods‐ Our group used the plasmid‐based miR inhibitor system (PMIS) to knock down specific miR‐200 family members in mice and study their role during developmental processes. Our system inhibits one miR within a cluster to understand the role of that miR, which cannot be accomplished using gene targeting methods.Results‐We inhibited the miR‐200 family in developing murine embryos using new technology, resulting in an expanded epithelial stem cell niche and lack of cell differentiation. Inhibition of individual miRs within the miR‐200 cluster resulted in differential developmental and cell morphology defects. miR‐200 inhibition increased the expression of dental epithelial stem cell markers, expanded the stem cell niche and decreased progenitor cell differentiation. RNA‐seq. identified miR‐200 regulatory pathways involved in cell differentiation and compartmentalization of the stem cell niche. The miR‐200 family regulates signaling pathways required for cell differentiation and cell cycle progression. New miR‐200targets demonstrate gene networks and pathways controlling cell differentiation and maintenance of the stem cell niche.Conclusion‐This is the first report demonstrating how the miR‐200 family is required for in vivo progenitor cell proliferation and differentiation.Significance/implication‐This new approach has identified several new scientific advancements in stem cell niche biology. 1) miR‐200 family members are required for in vivo epithelial stem cell differentiation and stem cell niche maintenance; 2) The miR‐200 family regulates genes required for generating the different dental epithelial cell lineages; 3) miR‐200expression may be a common mechanism for defining the boundaries of adult epithelial stem cell niches; 4) By inhibiting the miRs that become active when a progenitor cell becomes fated to differentiate, the in vivo cell differentiation programs are determined assuming their terminal fates; 5) Dental epithelial stem cells and suture stem cells are regulated by members of the miR‐200 family to yield the differentiated progeny and determine cell fate.

Dedifferentiation-mediated stem cell niche maintenance in early-stage ductal carcinoma in situ progression: insights from a multiscale modeling study

We present a multiscale agent-based model of ductal carcinoma in situ (DCIS) to study how key phenotypic and signaling pathways are involved in the early stages of disease progression. The model includes a phenotypic hierarchy, and key endocrine and paracrine signaling pathways, and simulates cancer ductal growth in a 3D lattice-free domain. In particular, by considering stochastic cell dedifferentiation plasticity, the model allows for study of how dedifferentiation to a more stem-like phenotype plays key roles in the maintenance of cancer stem cell populations and disease progression. Through extensive parameter perturbation studies, we have quantified and ranked how DCIS is sensitive to perturbations in several key mechanisms that are instrumental to early disease development. Our studies reveal that long-term maintenance of multipotent stem-like cell niches within the tumor are dependent on cell dedifferentiation plasticity, and that disease progression will become arrested due to dilution of the multipotent stem-like population in the absence of dedifferentiation. We have identified dedifferentiation rates necessary to maintain biologically relevant multipotent cell populations, and also explored quantitative relationships between dedifferentiation rates and disease progression rates, which may potentially help to optimize the efficacy of emerging anti-cancer stem cell therapeutics.