Composites and Structures for Regenerative Engineering

2014 ◽  
Vol 1621 ◽  
pp. 3-15 ◽  
Author(s):  
Cato T. Laurencin ◽  
Roshan James
Keyword(s):  
Cell Fate ◽  
Soft Tissues ◽  
De Novo ◽  
Control Cell ◽  
Continuous Phase ◽  
Lessons Learned ◽  
Regenerative Capacity ◽  
Regenerative Engineering ◽  
Organ Systems ◽  
Increasing Demand

ABSTRACTRegenerative engineering was conceptualized by bridging the lessons learned in developmental biology and stem cell science with biomaterial constructs and engineering principles to ultimately generate de novo tissue. We seek to incorporate our understanding of natural tissue development to design tissue-inducing biomaterials, structures and composites than can stimulate the regeneration of complex tissues, organs, and organ systems through location-specific topographies and physico-chemical cues incorporated into a continuous phase. This combination of classical top-down tissue engineering approach with bottom-up strategies used in regenerative biology represents a new multidisciplinary paradigm. Advanced surface topographies and material scales are used to control cell fate and the consequent regenerative capacity.Musculoskeletal tissues are critical to the normal functioning of an individual and following damage or degeneration they show extremely limited endogenous regenerative capacity. The increasing demand for biologically compatible donor tissue and organ transplants far outstrips the availability leading to an acute shortage. We have developed several biomimetic structures using various biomaterial platforms to combine optimal mechanical properties, porosity, bioactivity, and functionality to effect repair and regeneration of hard tissues such as bone, and soft tissues such as ligament and tendon. Starting with simple structures, we have developed composite and multi-scale systems that very closely mimic the native tissue architecture and material composition. Ultimately, we aim to modulate the regenerative potential, including proliferation, phenotype maturation, matrix production, and apoptosis through cell-scaffold and host –scaffold interactions developing complex tissues and organ systems.

scholarly journals Expanding the Clinical Spectrum of Sotos Syndrome in a Patient with the New “c.[5867T>A]+[=]”; “p.[Leu1956Gln]+[=]” NSD1 Missense Mutation and Complex Skin Hamartoma

2018 ◽  
Vol 19 (10) ◽  
pp. 3189
Author(s):  
Annalisa Mencarelli ◽  
Paolo Prontera ◽  
Amedea Mencarelli ◽  
Daniela Rogaia ◽  
Gabriela Stangoni ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Clinical Features ◽  
De Novo ◽  
Genetic Disorder ◽  
Control Cell ◽  
Functional Domain ◽  
Sotos Syndrome ◽  
Organ Systems ◽  
Increased Risk ◽  
The Right

Sotos syndrome is one of the most common overgrowth diseases and it predisposes patients to cancer, generally in childhood. The prevalence of this genetic disorder is 1:10,000–1:50,000, and it is characterized by wide allelic heterogeneity, with more than 100 different known mutations in the nuclear receptor-binding SET domain containing protein 1 (NSD1) gene. Most of these alterations are deletions and common micro-deletions with haploinsufficiency. Singular variants are missense mutations. The present study reports a case of a 4-year-old boy with specific clinical features of Sotos syndrome and a particular complex skin hamartoma on the right femoral side, in addition to other minor findings, such as a “café-au-lait” spot on the right hemithorax and syndactyly of the second and third right toes. NSD1 gene analysis identified a de novo missense mutation, “c.[5867T>A]+[=]”; “p.[Leu1956Gln]+[=]”, that was not previously described in the literature. This mutation was localized to the functional domain of the gene and was likely the cause of Sotos syndrome in our patient. We also compared aspects of our patient’s condition with the clinical features of tuberous sclerosis (TSC), which is an autosomal neurocutaneous syndrome caused by mutations in the TSC1/TSC2 genes. These genes control cell growth and cell survival. This disorder is characterized by hamartomas in multiple organ systems, several coetaneous abnormalities, epilepsy, and increased risk of several types of tumors.

The Evolution and Application of Regenerative Engineering

2014 ◽  
Vol 1687 ◽  
Author(s):  
Roshan James ◽  
Cato T. Laurencin
Keyword(s):  
Tissue Engineering ◽  
Stem Cell ◽  
Materials Science ◽  
Treatment Options ◽  
Continuous Phase ◽  
Tissue Loss ◽  
Regenerative Engineering ◽  
Musculoskeletal Tissues ◽  
Organ Systems ◽  
Multi Level

ABSTRACTCurrent treatment options for tissue loss or organ failure include organ/tissue transplantation of autografts/allografts, delivery of bioactive agents, and utilization of synthetic replacements composed of metals, polymers, and ceramics. However each strategy suffers from a number of limitations. The early attempts to overcome these drawbacks led to the emergence of tissue engineering that provided viable tissue substitutes using a combination of biomaterials, cells, and factors. This approach was ideally suited to repair damaged tissues; however the substitution and regeneration of large tissue volumes and multi-level tissues such as complex organ systems require more than optimal combinations of biomaterials and biologics.‘Regenerative Engineering’ is aimed at creating large and complex tissue systems incorporating advances in material science, stem cell technology and developmental biology. We believe that recent breakthrough technologies in advanced materials science and nanotechnology allow us to recapitulate native tissues. The novel designer polymers incorporate bioactivity and physical features specific to a regeneration application. Overall, engineered materials and scaffolds afford selective control of cell sensitivity, and precise control of temporal and spatial stimulatory cues. We aim to build multi-level systems such as organs through location-specific topographies and physico-chemical cues incorporated into a continuous phase using a combination of classical top-down tissue engineering approach with bottom-up strategies used in regenerative biology.Musculoskeletal tissues are critical to the normal functioning of an individual and following damage or degeneration show extremely limited endogenous regenerative capacity. The development of material and structural platforms to modulate stem cell behavior to enhance regeneration is an area of great interest. In this manuscript we cover some examples of material development, and incorporation of topographical and cytokine cues to modulate the differentiation of hard and soft musculoskeletal tissues such as bone, ligament and tendon.

scholarly journals TNFR1-d2 carrying the p.(Thr79Met) pathogenic variant is a potential novel actor of TNFα/TNFR1 signalling regulation in the pathophysiology of TRAPS

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Cécile Rittore ◽  
Déborah Méchin ◽  
Elodie Sanchez ◽  
Léa Marinèche ◽  
Vuthy Ea ◽  
...  
Keyword(s):  
Cell Fate ◽  
De Novo ◽  
Control Cell ◽  
Pathogenic Variant ◽  
Full Length ◽  
Entry Site ◽  
Gene Encoding ◽  
Exon 2 ◽  
Cell Fate Decisions ◽  
The Impact

AbstractBinding of tumour necrosis factor α (TNFα) to its receptor (TNFR1) is critical for both survival and death cellular pathways. TNFα/TNFR1 signalling is complex and tightly regulated at different levels to control cell fate decisions. Previously, we identified TNFR1-d2, an exon 2-spliced transcript of TNFRSF1A gene encoding TNFR1, whose splicing may be modulated by polymorphisms associated with inflammatory disorders. Here, we investigated the impact of TNFRSF1A variants involved in TNFR-associated periodic syndrome (TRAPS) on TNFR1-d2 protein expression and activity. We found that TNFR1-d2 could be translated by using an internal translation initiation codon and a de novo internal ribosome entry site (IRES), which resulted in a putative TNFR1 isoform lacking its N-terminal region. The kinetic of assembly of TNFR1-d2 clusters at the cell surface was reduced as compared with full-length TNFR1. Although co-localized with the full-length TNFR1, TNFR1-d2 neither activated nuclear factor (NF)-κB signalling, nor interfered with TNFR1-induced NF-κB activation. Translation of TNFR1-d2 carrying the severe p.(Thr79Met) pathogenic variant (also known as T50M) was initiated at the mutated codon, resulting in an elongated extracellular domain, increased speed to form preassembled clusters in absence of TNFα, and constitutive NF-κB activation. Overall, TNFR1-d2 might reflect the complexity of the TNFR1 signalling pathways and could be involved in TRAPS pathophysiology of patients carrying the p.(Thr79Met) disease-causing variant.

scholarly journals De novo TRPV4 Leu619Pro variant causes a new channelopathy characterised by giant cell lesions of the jaws and skull, skeletal abnormalities and polyneuropathy

2021 ◽  
pp. jmedgenet-2020-107427
Author(s):  
Aviel Ragamin ◽  
Carolina C Gomes ◽  
Karen Bindels-de Heus ◽  
Renata Sandoval ◽  
Angelia V Bassenden ◽  
...  
Keyword(s):  
Giant Cell ◽  
De Novo ◽  
Neuromuscular Disorders ◽  
Somatic Mosaicism ◽  
Ion Leakage ◽  
Gain Of Function ◽  
Therapeutic Modalities ◽  
Organ Systems ◽  
Heterozygous Variant ◽  
Systemic Disorder

BackgroundPathogenic germline variants in Transient Receptor Potential Vanilloid 4 Cation Channel (TRPV4) lead to channelopathies, which are phenotypically diverse and heterogeneous disorders grossly divided in neuromuscular disorders and skeletal dysplasia. We recently reported in sporadic giant cell lesions of the jaws (GCLJs) novel, somatic, heterozygous, gain-of-function mutations in TRPV4, at Met713.MethodsHere we report two unrelated women with a de novo germline p.Leu619Pro TRPV4 variant and an overlapping systemic disorder affecting all organs individually described in TRPV4 channelopathies.ResultsFrom an early age, both patients had several lesions of the nervous system including progressive polyneuropathy, and multiple aggressive giant cell-rich lesions of the jaws and craniofacial/skull bones, and other skeletal lesions. One patient had a relatively milder disease phenotype possibly due to postzygotic somatic mosaicism. Indeed, the TRPV4 p.Leu619Pro variant was present at a lower frequency (variant allele frequency (VAF)=21.6%) than expected for a heterozygous variant as seen in the other proband, and showed variable regional frequency in the GCLJ (VAF ranging from 42% to 10%). In silico structural analysis suggests that the gain-of-function p.Leu619Pro alters the ion channel activity leading to constitutive ion leakage.ConclusionOur findings define a novel polysystemic syndrome due to germline TRPV4 p.Leu619Pro and further extend the spectrum of TRPV4 channelopathies. They further highlight the convergence of TRPV4 mutations on different organ systems leading to complex phenotypes which are further mitigated by possible post-zygotic mosaicism. Treatment of this disorder is challenging, and surgical intervention of the GCLJ worsens the lesions, suggesting the future use of MEK inhibitors and TRPV4 antagonists as therapeutic modalities for unmet clinical needs.

scholarly journals Notch signaling coordinates ommatidial rotation in the Drosophila eye via transcriptional regulation of the EGF-Receptor ligand Argos

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yildiz Koca ◽  
Benjamin E. Housden ◽  
William J. Gault ◽  
Sarah J. Bray ◽  
Marek Mlodzik
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Planar Cell Polarity ◽  
Egf Receptor ◽  
Control Cell ◽  
Loss Of Function ◽  
Egfr Signaling ◽  
Specific Expression ◽  
Egfr Signaling Pathway ◽  
Ommatidial Rotation

AbstractIn all metazoans, a small number of evolutionarily conserved signaling pathways are reiteratively used during development to orchestrate critical patterning and morphogenetic processes. Among these, Notch (N) signaling is essential for most aspects of tissue patterning where it mediates the communication between adjacent cells to control cell fate specification. In Drosophila, Notch signaling is required for several features of eye development, including the R3/R4 cell fate choice and R7 specification. Here we show that hypomorphic alleles of Notch, belonging to the Nfacet class, reveal a novel phenotype: while photoreceptor specification in the mutant ommatidia is largely normal, defects are observed in ommatidial rotation (OR), a planar cell polarity (PCP)-mediated cell motility process. We demonstrate that during OR Notch signaling is specifically required in the R4 photoreceptor to upregulate the transcription of argos (aos), an inhibitory ligand to the epidermal growth factor receptor (EGFR), to fine-tune the activity of EGFR signaling. Consistently, the loss-of-function defects of Nfacet alleles and EGFR-signaling pathway mutants are largely indistinguishable. A Notch-regulated aos enhancer confers R4 specific expression arguing that aos is directly regulated by Notch signaling in this context via Su(H)-Mam-dependent transcription.

scholarly journals Positive Feedback Between PU.1 and the Cell Cycle Controls Myeloid Differentiation

Science ◽  
2013 ◽  
Vol 341 (6146) ◽  
pp. 670-673 ◽  
Author(s):  
Hao Yuan Kueh ◽  
Ameya Champhekar ◽  
Stephen L. Nutt ◽  
Michael B. Elowitz ◽  
Ellen V. Rothenberg
Keyword(s):  
Cell Cycle ◽  
Cell Fate ◽  
Positive Feedback ◽  
Regulatory Gene ◽  
Control Cell ◽  
Stem Cell Differentiation ◽  
Myeloid Differentiation ◽  
Cycle Duration ◽  
Gene Circuits ◽  
Cell Cycles

Regulatory gene circuits with positive-feedback loops control stem cell differentiation, but several mechanisms can contribute to positive feedback. Here, we dissect feedback mechanisms through which the transcription factor PU.1 controls lymphoid and myeloid differentiation. Quantitative live-cell imaging revealed that developing B cells decrease PU.1 levels by reducing PU.1 transcription, whereas developing macrophages increase PU.1 levels by lengthening their cell cycles, which causes stable PU.1 accumulation. Exogenous PU.1 expression in progenitors increases endogenous PU.1 levels by inducing cell cycle lengthening, implying positive feedback between a regulatory factor and the cell cycle. Mathematical modeling showed that this cell cycle–coupled feedback architecture effectively stabilizes a slow-dividing differentiated state. These results show that cell cycle duration functions as an integral part of a positive autoregulatory circuit to control cell fate.

scholarly journals Context-dependent roles of YAP/TAZ in stem cell fates and cancer

2021 ◽  
Author(s):  
Lucy LeBlanc ◽  
Nereida Ramirez ◽  
Jonghwan Kim
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Control Cell ◽  
Substantial Portion ◽  
Cell Fates ◽  
Cell Fate Decisions ◽  
Cell Death Pathways ◽  
Multiple Context ◽  
Cancer Cell Survival ◽  
Context Dependent

AbstractHippo effectors YAP and TAZ control cell fate and survival through various mechanisms, including transcriptional regulation of key genes. However, much of this research has been marked by conflicting results, as well as controversy over whether YAP and TAZ are redundant. A substantial portion of the discordance stems from their contradictory roles in stem cell self-renewal vs. differentiation and cancer cell survival vs. apoptosis. In this review, we present an overview of the multiple context-dependent functions of YAP and TAZ in regulating cell fate decisions in stem cells and organoids, as well as their mechanisms of controlling programmed cell death pathways in cancer.

Super-Enhancer-Associated Transcription Factors Maintain Transcriptional Regulation in Mature Podocytes

2021 ◽  
pp. ASN.2020081177
Author(s):  
Jingping Yang ◽  
Difei Zhang ◽  
Masaru Motojima ◽  
Tsutomu Kume ◽  
Qing Hou ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Animal Models ◽  
Cell Fate ◽  
Control Cell ◽  
Transgenic Animal ◽  
Animal Models Of Disease ◽  
Super Enhancer ◽  
Models Of Disease ◽  
Human Glomerulus

BackgroundTranscriptional programs control cell fate, and identifying their components is critical for understanding diseases caused by cell lesion, such as podocytopathy. Although many transcription factors (TFs) are necessary for cell-state maintenance in glomeruli, their roles in transcriptional regulation are not well understood.MethodsThe distribution of H3K27ac histones in human glomerulus cells was analyzed to identify superenhancer-associated TFs, and ChIP-seq and transcriptomics were performed to elucidate the regulatory roles of the TFs. Transgenic animal models of disease were further investigated to confirm the roles of specific TFs in podocyte maintenance.ResultsSuperenhancer distribution revealed a group of potential TFs in core regulatory circuits in human glomerulus cells, including FOXC1/2, WT1, and LMX1B. Integration of transcriptome and cistrome data of FOXC1/2 in mice resolved transcriptional regulation in podocyte maintenance. FOXC1/2 regulated differentiation-associated transcription in mature podocytes. In both humans and animal models, mature podocyte injury was accompanied by deregulation of FOXC1/2 expression, and FOXC1/2 overexpression could protect podocytes in zebrafish.ConclusionsFOXC1/2 maintain podocyte differentiation through transcriptional stabilization. The genome-wide chromatin resources support further investigation of TFs’ regulatory roles in glomeruli transcription programs.

A regulatory network of microRNAs confers lineage commitment during early developmental trajectories of B and T lymphocytes

2021 ◽  
Vol 118 (46) ◽  
pp. e2104297118
Author(s):  
Sameena Nikhat ◽  
Anurupa D. Yadavalli ◽  
Arpita Prusty ◽  
Priyanka K. Narayan ◽  
Dasaradhi Palakodeti ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Lymphocytes ◽  
Cell Fate ◽  
T Lymphocyte ◽  
De Novo ◽  
Gene Expression Pattern ◽  
Lymphocyte Development ◽  
Motif Analysis ◽  
Differentiation Potential ◽  
B And T Lymphocytes

The commitment of hematopoietic multipotent progenitors (MPPs) toward a particular lineage involves activation of cell type–specific genes and silencing of genes that promote alternate cell fates. Although the gene expression programs of early–B and early–T lymphocyte development are mutually exclusive, we show that these cell types exhibit significantly correlated microRNA (miRNA) profiles. However, their corresponding miRNA targetomes are distinct and predominated by transcripts associated with natural killer, dendritic cell, and myeloid lineages, suggesting that miRNAs function in a cell-autonomous manner. The combinatorial expression of miRNAs miR-186-5p, miR-128-3p, and miR-330-5p in MPPs significantly attenuates their myeloid differentiation potential due to repression of myeloid-associated transcripts. Depletion of these miRNAs caused a pronounced de-repression of myeloid lineage targets in differentiating early–B and early–T cells, resulting in a mixed-lineage gene expression pattern. De novo motif analysis combined with an assay of promoter activities indicates that B as well as T lineage determinants drive the expression of these miRNAs in lymphoid lineages. Collectively, we present a paradigm that miRNAs are conserved between developing B and T lymphocytes, yet they target distinct sets of promiscuously expressed lineage-inappropriate genes to suppress the alternate cell-fate options. Thus, our studies provide a comprehensive compendium of miRNAs with functional implications for B and T lymphocyte development.

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