Adult Neural Stem Cell Regulation by Small Non-coding RNAs: Physiological Significance and Pathological Implications

The adult neurogenic niches are complex multicellular systems, receiving regulatory input from a multitude of intracellular, juxtacrine, and paracrine signals and biological pathways. Within the niches, adult neural stem cells (aNSCs) generate astrocytic and neuronal progeny, with the latter predominating in physiological conditions. The new neurons generated from this neurogenic process are functionally linked to memory, cognition, and mood regulation, while much less is known about the functional contribution of aNSC-derived newborn astrocytes and adult-born oligodendrocytes. Accumulating evidence suggests that the deregulation of aNSCs and their progeny can impact, or can be impacted by, aging and several brain pathologies, including neurodevelopmental and mood disorders, neurodegenerative diseases, and also by insults, such as epileptic seizures, stroke, or traumatic brain injury. Hence, understanding the regulatory underpinnings of aNSC activation, differentiation, and fate commitment could help identify novel therapeutic avenues for a series of pathological conditions. Over the last two decades, small non-coding RNAs (sncRNAs) have emerged as key regulators of NSC fate determination in the adult neurogenic niches. In this review, we synthesize prior knowledge on how sncRNAs, such as microRNAs (miRNAs) and piwi-interacting RNAs (piRNAs), may impact NSC fate determination in the adult brain and we critically assess the functional significance of these events. We discuss the concepts that emerge from these examples and how they could be used to provide a framework for considering aNSC (de)regulation in the pathogenesis and treatment of neurological diseases.

Role of Rho GTPases in stem cell regulation

The future of regenerative medicine relies on our understanding of stem cells which are essential for tissue/organ generation and regeneration to maintain and/or restore tissue homeostasis. Rho family GTPases are known regulators of a wide variety of cellular processes related to cytoskeletal dynamics, polarity and gene transcription. In the last decade, major new advances have been made in understanding the regulatory role and mechanism of Rho GTPases in self-renewal, differentiation, migration, and lineage specification in tissue-specific signaling mechanisms in various stem cell types to regulate embryonic development, adult tissue homeostasis, and tissue regeneration upon stress or damage. Importantly, implication of Rho GTPases and their upstream regulators or downstream effectors in the transformation, migration, invasion and tumorigenesis of diverse cancer stem cells highlights the potential of Rho GTPase targeting in cancer therapy. In this review, we discuss recent evidence of Rho GTPase signaling in the regulation of embryonic stem cells, multiple somatic stem cells, and cancer stem cells. We propose promising areas where Rho GTPase pathways may serve as useful targets for stem cell manipulation and related future therapies.

IL2 Neural stem cell regulation and brain development

Quiescent neural stem cells (NSCs) in the adult mouse brain are the source of neurogenesis that regulates innate and adaptive behaviors. Adult NSCs in the subventricular zone (SVZ) are derived from a subpopulation of embryonic neural stem-progenitor cells (NPCs) that is characterized by a slower cell cycle relative to the more abundant rapid cycling NPCs that build the brain. We have previously shown that slow cell cycle can cause the establishment of adult NSCs at the SVZ, although the underlying mechanism remains unknown. We found that Notch and an effector Hey1 form a module that is upregulated by cell cycle arrest in slowly dividing NPCs. In contrast to the oscillatory expression of the Notch effectors Hes1 and Hes5 in fast cycling progenitors, Hey1 displays a non-oscillatory stationary expression pattern and contributes to the long-term maintenance of NSCs. These findings reveal a novel division of labor in Notch effectors where cell cycle rate biases effector selection and cell fate. I will also discuss the heterogeneity of slowly dividing embryonic NPCs and the lineage relationship between adult NSCs and ependymal cells, which together form the niche for adult neurogenesis at the SVZ.

Identification of a new allele of O-fucosyltransferase 1 involved in Drosophila intestinal stem cell regulation

ABSTRACT Adult stem cells are critical for the maintenance of tissue homeostasis. However, how the proliferation and differentiation of intestinal stem cells (ISCs) are regulated remains not fully understood. Here, we find a mutant, stum 9-3, affecting the proliferation and differentiation of Drosophila adult ISCs in a forward genetic screen for factors regulating the proliferation and differentiation ISCs. stum 9-3 acts through the conserved Notch signaling pathway, upstream of the S2 cleavage of the Notch receptor. Interestingly, the phenotype of stum 9-3 mutant is not caused by disruption of stumble (stum), where the p-element is inserted. Detailed mapping, rescue experiments and mutant characterization show that stum 9-3 is a new allele of O-fucosyltransferase 1 (O-fut1). Our results indicate that unexpected mutants with interesting phenotype could be recovered in forward genetic screens using known p-element insertion stocks.

The role of R-spondin proteins in cancer biology

R-spondin (RSPO) proteins constitute a family of four secreted glycoproteins (RSPO1–4) that have appeared as multipotent signaling ligands. The best-known molecular function of RSPOs lie within their capacity to agonize the Wnt/β-catenin signaling pathway. As RSPOs act upon cognate receptors LGR4/5/6 that are typically expressed by stem cells and progenitor cells, RSPO proteins importantly potentiate Wnt/β-catenin signaling especially within these proliferative stem cell compartments. Since multiple organs express LGR4/5/6 receptors and RSPO ligands within their stem cell niches, RSPOs can exert an influential role in stem cell regulation throughout the body. Inherently, over the last decade a multitude of reports implicated the deregulation of RSPOs in cancer development. First, RSPO2 and RSPO3 gene fusions with concomitant enhanced expression have been identified in colon cancer patients, and proposed as an alternative driver of Wnt/β-catenin hyperactivation that earmarks cancer in the colorectal tract. Moreover, the causal oncogenic capacity of RSPO3 overactivation has been demonstrated in the mouse intestine. As a paradigm organ in this field, most of current knowledge about RSPOs in cancer is derived from studies in the intestinal tract. However, RSPO gene fusions as well as enhanced RSPO expression have been reported in multiple additional cancer types, affecting different organs that involve divergent stem cell hierarchies. Importantly, the emerging oncogenic role of RSPO and its potential clinical utility as a therapeutic target have been recognized and investigated in preclinical and clinical settings. This review provides a survey of current knowledge on the role of RSPOs in cancer biology, addressing the different organs implicated, and of efforts made to explore intervention opportunities in cancer cases with RSPO overrepresentation, including the potential utilization of RSPO as novel therapeutic target itself.

Understanding neural stem cell regulation in vivo and applying the insights to cell therapy for strokes

The use of neural stem cell (NSC) therapy for the treatment of stroke patients is successfully paving its way into advanced phases of large-scale clinical trials. To understand how to optimize NSC therapeutic approaches, it is fundamental to decipher the crosstalk between NSC and other cells that comprise the NSC microenvironment (niche) and regulate their function, in vivo; namely, the endothelial cells of the microvasculature. In this mini review, we first provide a concise summary of preclinical findings describing the signaling mechanisms between NSC and vascular endothelial cells and vice versa. Second, we describe the progress made in the development of NSC therapy for the treatment of strokes.

Non-Coding RNAs in Stem Cell Regulation and Cardiac Regeneration: Current Problems and Future Perspectives

Although advances in rapid revascularization strategies following acute myocardial infarction (AMI) have led to improved short and long-term outcomes, the associated loss of cardiomyocytes and the subsequent remodeling result in an impaired ventricular function that can lead to heart failure or death. The poor regenerative capacity of the myocardium and the current lack of effective regenerative therapies have driven stem cell research in search of a possible solution. One approach involves the delivery of stem cells to the site of injury in order to stimulate repair response. Although animal studies initially delivered promising results, the application of similar techniques in humans has been hampered by poor target site retention and oncogenic considerations. In response, several alternative strategies, including the use of non-coding RNAs (ncRNAs), have been introduced with the aim of activating and regulating stem cells or inducing stem cell status in resident cells. Circular RNAs (circRNAs) and microRNAs (miRNAs) are ncRNAs with pivotal functions in cell proliferation and differentiation, whose role in stem cell regulation and potential significance for the field of cardiac regeneration is the primary focus of this review. We also address the general advantages of ncRNAs as promising drivers of cardiac regeneration and potent stem cell regulators.

Vascular Cambium: The Source of Wood Formation

Wood is the most abundant biomass produced by land plants and is mainly used for timber, pulping, and paper making. Wood (secondary xylem) is derived from vascular cambium, and its formation encompasses a series of developmental processes. Extensive studies in Arabidopsis and trees demonstrate that the initiation of vascular stem cells and the proliferation and differentiation of the cambial derivative cells require a coordination of multiple signals, including hormones and peptides. In this mini review, we described the recent discoveries on the regulation of the three developmental processes by several signals, such as auxin, cytokinins, brassinosteroids, gibberellins, ethylene, TDIF peptide, and their cross talk in Arabidopsis and Populus. There exists a similar but more complex regulatory network orchestrating vascular cambium development in Populus than that in Arabidopsis. We end up with a look at the future research prospects of vascular cambium in perennial woody plants, including interfascicular cambium development and vascular stem cell regulation.