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MicroRNAs (miRNAs) are small single-stranded non-coding RNAs around 22 nucleotide lengths found in organisms, playing an important role in cell differentiation, development, gene regulation, and apoptosis. The distance of disease miRNA biomarkers has been used to explore the association between various diseases as well as the association between virus and disease in the literature. To date, there have been no studies on deriving the distribution of the pairwise distance of human miRNAs. As the pairwise distance of miRNA biomarkers might be a useful tool in studying the disease association, in this paper, the distance distributions of human miRNAs were derived such that they could be used to measure the closeness between miRNAs. Two distance models were used to calculate the pairwise distances of 567 Homo sapiens miRNA genes accessed from the MirGeneDB database. These miRNA pairwise distances were fitted by the normal distribution, gamma distribution, empirical cumulative distribution, and the kernel density estimation method. This is the first study to provide the distance distribution of human miRNAs. The similarity of miRNA biomarkers for several diseases was examined using the derived distributions.

Cell state transitions induced by mechano-chemical cues result in a heterogeneous population of cell states. While much of the work towards understanding the origins of such heterogeneity has focused on the gene regulatory mechanisms, the contribution of intrinsic mechanical properties of cells remains unknown. In this paper, using a well-defined single cell platform to induce cell-state transitions, we reveal the importance of actomyosin contractile forces in regulating the heterogeneous cell-fate decisions. Temporal analysis of laterally confined growth of fibroblasts revealed sequential changes in the colony morphology which was tightly coupled to the progressive erasure of lineage-specific transcription programs. Pseudo-trajectory constructed using unsupervised diffusion analysis of the colony morphology features revealed a bifurcation event in which some cells undergo successful cell state transitions towards partial reprogramming. Importantly, inhibiting actomyosin contractility before the bifurcation event leads to more efficient dedifferentiation. Taken together, this study highlights the presence of mechanical checkpoints that contribute to the heterogeneity in cell state transitions., Scientific Reports, 12 (1), ISSN:2045-2322

Magnetic nanomaterials are increasingly impacting the field of biology and medicine. Their versatility in terms of shape, structure, composition, coating, and magnetic responsivity make them attractive for drug delivery, cell targeting and imaging. Adipose derived-mesenchymal cells (ASCs) are intensely scrutinized for tissue engineering and regenerative medicine. However, differentiation into musculoskeletal lineages can be challenging. In this paper, we show that uncoated nickel nanowires (Ni NW) partially released from their alumina membrane offer a mechanically-responsive substrate with regular topography that can be used for the delivery of magneto-mechanical stimulation. We have used a tailored protocol for improving ASCs adherence to the substrate, and showed that cells retain their characteristic fibroblastic appearance, cytoskeletal fiber distribution and good viability. We report here for the first time significant increase in osteogenic but not adipogenic differentiation of ASCs on Ni NW exposed to 4 mT magnetic field compared to non-exposed. Moreover, magnetic actuation is shown to induce ASCs osteogenesis but not adipogenesis in the absence of external biochemical cues. While these findings need to be verified in vivo, the use of Ni NW substrate for inducing osteogenesis in the absence of specific differentiation factors is attractive for bone engineering. Implant coating with similar surfaces for orthopedic and dentistry could be as well envisaged as a modality to improve osteointegration.

Cold atmospheric plasma has established its effect on cell adhesion. Given the importance of cell adhesion in stem cells, the current study investigates the effect of plasma treatment on Human Bone Marrow Mesenchymal Stem Cells (HBMMSCs) adhesion by which the differentiation and fate of cells are determined. In this paper, adhesion modification is considered not only for cell- ECM (Extra cellular Matrix), but also between suspended cells, and enhanced adhesions were found in both circumstances. Regarding the previous works, the increase of the cell–ECM adhesion during the plasma therapy was mostly attributed to the enhancement of the production and activity of integrin proteins. Nevertheless, considering the importance of van der Waals forces at the cellular level, the effect of cold plasma on VDWFs and so its effect on adhesion is investigated in this work for the first time, to the best of our knowledge. For this purpose, employing the semi-empirical methods, the role of the plasma therapy on the VDWF between the cells has been studied at three levels; (a) plasma-induced dipole formation, (b) Hammaker coefficient modification of culture medium, and c) cell roughness modification. For suspended cell condition, we conclude and support that van der Waals forces (VDWFs) enhancement has a key role in cell adhesion processes. We believe that, the present work gives a new physical insight in studying the plasma therapy method at the cellular level.

With a five-year survival rate of 9%, pancreatic ductal adenocarcinoma (PDAC) is the deadliest of all cancers. The rapid mortality makes PDAC difficult to research, and inspires a resolve to create reliable, tractable cellular models for preclinical cancer research. Organoids are increasingly used to model PDAC as they maintain the differentiation status, molecular and genomic signatures of the original tumour. In this paper, we present novel methodologies and experimental approaches to develop PDAC organoids from PDX tumours, and the simultaneous development of matched primary cell lines. Moreover, we also present a method of recapitulating primary cell line cultures to organoids (CLOs). We highlight the usefulness of CLOs as PDAC organoid models, as they maintain similar transcriptomic signatures as their matched patient-derived organoids and patient derived xenografts (PDX)s. These models provide a manageable, expandable in vitro resource for downstream applications such as high throughput screening, functional genomics, and tumour microenvironment studies.

The process of stem cell myogenesis (transformation into skeletal muscle cells) includes several stages characterized by the expression of certain combinations of myogenic factors. The first part of this process is accompanied by cell division, while the second part is mainly associated with direct differentiation. The mechanical cues are known to enhance stem cell myogenesis, and the paper focuses on the stem cell differentiation under the condition of externally applied strain. The process of stem cell myogenic differentiation is interpreted as the interplay among transcription factors, targeted proteins and strain-generated signaling molecule, and it is described by a kinetic multi-stage model. The model parameters are optimally adjusted by using the available data from the experiment with adipose-derived stem cells subjected to the application of cyclic uniaxial strains of the magnitude of 10%. The modeling results predict the kinetics of the process of myogenic differentiation, including the number of cells in each stage of differentiation and the rates of differentiation from one stage to another for different strains from 4% to 16%. The developed model can help better understand the process of myogenic differentiation and the effects of mechanical cues on stem cell use in muscle therapies.

Human induced pluripotent stem cells (iPSCs) are ideal cell sources for personalized cell therapies since they can be expanded to generate large numbers of cells and differentiated into presumably all the cell types of the human body in vitro. In addition, patient specific iPSC-derived cells induce minimal or no immune response in vivo. However, with current cell culture technologies and bioprocessing, the cost for biomanufacturing clinical-grade patient specific iPSCs and their derivatives are very high and not affordable for majority of patients. In this paper, we explored the use of closed and miniature cell culture device for biomanufacturing patient specific neural stem cells (NSCs) from iPSCs. We demonstrated that, with the assist of a thermoreversible hydrogel scaffold, the bioprocessing including iPSC expansion, iPSC differentiation into NSCs, the subsequent depletion of undifferentiated iPSCs from the NSCs, and concentrating and transporting the purified NSCs to the surgery room, could be integrated and completed within two closed 15 ml conical tubes.

A few central transcription factors inside mouse embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are believed to control the cells’ pluripotency. Characterizations of pluripotent state were put forward on both transcription factor and epigenetic levels. Whereas core players have been identified, it is desirable to map out gene regulatory networks which govern the reprogramming of somatic cells as well as the early developmental decisions. Here we propose a multiple level model where the regulatory network of Oct4, Nanog and Tet1 includes positive feedback loops involving DNA-demethylation around the promoters of Oct4 and Tet1. We put forward a mechanistic understanding of the regulatory dynamics which account for i) Oct4 overexpression is sufficient to induce pluripotency in somatic cell types expressing the other Yamanaka reprogramming factors endogenously; ii) Tet1 can replace Oct4 in reprogramming cocktail; iii) Nanog is not necessary for reprogramming however its over-expression leads to enhanced self-renewal; iv) DNA methylation is the key to the regulation of pluripotency genes; v) Lif withdrawal leads to loss of pluripotency. Overall, our paper proposes a novel framework combining transcription regulation with DNA methylation modifications which, takes into account the multi-layer nature of regulatory mechanisms governing pluripotency acquisition through reprogramming.

Intradermal adipose tissue plays an essential role for hair follicles (HFs) regeneration by regulating hair cycles. However, the effect of reconstruction of HFs and the involvement of adipose-related cells are poorly understood. We investigated assembly strategies for the interactions of dermal papilla (DP) cells with adipose-derived stem cells (ASCs) in promoting hair formation. DP cells lose DP traits during adherent culture, but preserved DP markers with a unified sphere diameter by seeding on chitosan-coated microenvironments. Next, ASCs isolated from rats were co-cultured with DP spheres by different assembling approaches to determine their interactions; a mixed sphere of ASCs with DP cells (MA-DPS), or a core-shell structure, outer ASCs shell and an inner DP core (CSA-DPS). CSA-DPS exhibited superior DP characteristics compared to MA-DPS. Conditional medium from ASCs, but not differentiated adipocytes, promoted DP markers and functional alkaline phosphatase activity from the DP cells. In vivo patch assay showed the core-shell assembling of CSA-DPS can reconstruct cellular arrangements and microenvironmental niches as dominated by PPARα signal in ASCs to induce the greater hair induction than MA-DPS or DP spheres alone. Therefore, the assembling of a core-shell sphere for DP with ASCs could reconstruct the HF cellular arrangement for hair formation. This paper set the groundwork for further evaluation of the input of other cell types.