MicroRNAs in neural stem cell proliferation and differentiation

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that are emerging as key regulators of neural (stem) cell properties. Due to their ability to regulate a broad repertoire of targets, they represent an exciting tool to modulate stem cell fate. Brain-enriched miR-9/9* has been described to enhance neural stem cell differentiation and impact on regionalization. Furthermore, it was suggested to interact with the Notch signaling pathway, which is well known to play a fundamental role in neural stem cell maintenance and differentiation. To investigate a potential miRNA-Notch-interplay, a Notch-dependent population of neuroepithelial stem cells derived from human embryonic stem (lt-NES) cells was chosen as a model system. In line with previous findings, ectopic expression of miR-9/9* impaired self-renewal and promoted differentiation of lt-NES cells. Our analysis revealed that this impact of miR-9/9* is, at least in part, due to a feedback loop between miR-9/9* and Notch activity. Notch directly controls miR-9/9* expression on a transcriptional level, while miR-9/9* in turn regulates Notch signaling by targeting of HES1 and NOTCH2. However, elevated levels of individual miR-9 and miR-9* revealed a separate way of action. While miR-9 enhanced differentiation and targeted HES1 and NOTCH2, miR-9* enhanced differentiation, impaired self-renewal of lt-NES cells and was shown to target NOTCH2 and SOX2. Compared to other miRNAs identified in a miRNA expression profiling during lt-NES cell differentiation (i.e. miR-7, miR-128, and miR-130b), only elevated levels of miR-9/9* induced significant changes in lt-NES proliferation and spontaneous differentiation. Nevertheless, long-term (15 days) lt-NES cell differentiation was enhanced by miR-9/9* as well as miR-7. Detailed analysis revealed that they even affect neuronal subtype specification. While the overall number of differentiated neurons increased, the generation of neurons positive for dopaminergic marker TH was impaired upon miR-9/9* and miR-7 overexpression. In line with this, miR-9, miR-9*, and miR-7 were downregulated during the time course of a floor plate precursor based differentiation protocol for the generation of mesencephalic dopaminergic neurons from human pluripotent stem cells. Futhermore, overexpression of miR-9/9* and miR-7 reduced mRNA expression levels of EN2 and FOXA2, two additional dopaminergic markers. Taken together, these results show that miRNAs can be used to modulate human neural stem cell maintenance, differentiation and subtype specification. Specifically, miR-9 and miR-9* act on human neural stem cell maintenance and spontaneous differentiation – to some extent by their interplay with the Notch signaling pathway. In addition, miR-9/9* as well as miR-7 impact on neural stem cell differentiation and lineage decision

Recommendations for optimal interdisciplinary management and healthcare settings for patients with rare neurological diseases

BackgroundIn 2017, the German Academy for Rare Neurological Diseases (Deutsche Akademie fur Seltene Neurologische Erkrankungen;DASNE) was founded to pave the way for an optimized personalized management of patients with rare neurological diseases (RND) in all age groups. Since then a dynamic national network for rare neurological disorders has been established comprising renowned experts in neurology, pediatric neurology, (neuro-) genetics and neuroradiology. DASNE has successfully implemented case presentations and multidisciplinary discussions both at yearly symposia and monthly virtual case conferences, as well as further educational activities covering a broad spectrum of interdisciplinary expertise associated with RND. Here, we present recommendation statements for optimized personalized management of patients with RND, which have been developed and reviewed in a structured Delphi process by a group of experts.MethodsAn interdisciplinary group of 37 RND experts comprising DASNE experts, patient representatives, as well as healthcare professionals and managers was involved in the Delphi process. First, an online collection was performed of topics considered relevant for optimal patient care by the expert group. Second, a two-step Delphi process was carried out to rank the importance of the selected topics. Small interdisciplinary working groups then drafted recommendations. In two consensus meetings and one online review round these recommendations were finally consented.Results38 statements were consented and grouped into 11 topics: health care structure, core neurological expertise and core mission, interdisciplinary team composition, diagnostics, continuous care and therapy development, case conferences, exchange / cooperation between Centers for Rare Diseases and other healthcare partners, patient advocacy group, databases, translation and health policy.ConclusionsThis German interdisciplinary Delphi expert panel developed consented recommendations for optimal care of patients with RND in a structured Delphi process. These represent a basis for further developments and adjustments in the health care system to improve care for patients with RND and their families

Reported positive (blue), negative (orange) and nondirectional (purple) consequences of team flow.

Reported positive (blue), negative (orange) and nondirectional (purple) consequences of team flow.</p

Interview guideline.

Flow experience is a state of complete absorption while performing an optimally challenging and enjoyable task. It is often experienced at work—both in the form of individual and team flow—and can have a positive effect on performance and well-being. However, start-up founders’ work situation differs from that in established companies, facing not only great autonomy but also new challenges, uncertainty, and risks. It can be assumed that flow also provides benefits in start-ups, however, this has not yet been examined in depth and the factors that may operate differently in start-ups in comparison to other work contexts have not yet been explored in detail. Using a qualitative research approach, 21 founders from different industries were interviewed. Enhancing and inhibiting factors of flow and team flow as well as consequences for the founders and the start-up in general were examined and structured with the help of a qualitative content analysis. A variety of contexts was identified in which founders experienced flow and team flow. Various factors on the individual, task-related and organizational sphere were found to be perceived as promoting or hindering flow and team flow, e.g. well-being, autonomy or the environment. The findings regarding the consequences of flow and team flow show that these mainly are very desirable states for founders, e.g. leading to better results, progress or team processes. Only few negative consequences were identified, e.g. perfectionism. Thus, it is helpful to foster flow in the start-up context. Possible approaches derived from the participants’ statements to this could be, for example, to design flow-promoting environments or participation in specific workshops.</div

Reported positive (blue), negative (orange), and nondirectional (purple) consequences of flow.

Reported positive (blue), negative (orange), and nondirectional (purple) consequences of flow.</p

Codebook.

Flow experience is a state of complete absorption while performing an optimally challenging and enjoyable task. It is often experienced at work—both in the form of individual and team flow—and can have a positive effect on performance and well-being. However, start-up founders’ work situation differs from that in established companies, facing not only great autonomy but also new challenges, uncertainty, and risks. It can be assumed that flow also provides benefits in start-ups, however, this has not yet been examined in depth and the factors that may operate differently in start-ups in comparison to other work contexts have not yet been explored in detail. Using a qualitative research approach, 21 founders from different industries were interviewed. Enhancing and inhibiting factors of flow and team flow as well as consequences for the founders and the start-up in general were examined and structured with the help of a qualitative content analysis. A variety of contexts was identified in which founders experienced flow and team flow. Various factors on the individual, task-related and organizational sphere were found to be perceived as promoting or hindering flow and team flow, e.g. well-being, autonomy or the environment. The findings regarding the consequences of flow and team flow show that these mainly are very desirable states for founders, e.g. leading to better results, progress or team processes. Only few negative consequences were identified, e.g. perfectionism. Thus, it is helpful to foster flow in the start-up context. Possible approaches derived from the participants’ statements to this could be, for example, to design flow-promoting environments or participation in specific workshops.</div

Fig 1 -

Derivation of the research questions from the relationship between start-up factors and flow and team flow in an input-process-outcome model.</p

The interview guideline.

Flow experience is a state of complete absorption while performing an optimally challenging and enjoyable task. It is often experienced at work—both in the form of individual and team flow—and can have a positive effect on performance and well-being. However, start-up founders’ work situation differs from that in established companies, facing not only great autonomy but also new challenges, uncertainty, and risks. It can be assumed that flow also provides benefits in start-ups, however, this has not yet been examined in depth and the factors that may operate differently in start-ups in comparison to other work contexts have not yet been explored in detail. Using a qualitative research approach, 21 founders from different industries were interviewed. Enhancing and inhibiting factors of flow and team flow as well as consequences for the founders and the start-up in general were examined and structured with the help of a qualitative content analysis. A variety of contexts was identified in which founders experienced flow and team flow. Various factors on the individual, task-related and organizational sphere were found to be perceived as promoting or hindering flow and team flow, e.g. well-being, autonomy or the environment. The findings regarding the consequences of flow and team flow show that these mainly are very desirable states for founders, e.g. leading to better results, progress or team processes. Only few negative consequences were identified, e.g. perfectionism. Thus, it is helpful to foster flow in the start-up context. Possible approaches derived from the participants’ statements to this could be, for example, to design flow-promoting environments or participation in specific workshops.</div

Start-up factors enhancing flow (green) and inhibiting flow (red).

Start-up factors enhancing flow (green) and inhibiting flow (red).</p

Start-up factors enhancing team flow (green) and inhibiting team flow (red).

Start-up factors enhancing team flow (green) and inhibiting team flow (red).</p