scholarly journals A Paradigm Shift in Tissue Engineering: From a Top–Down to a Bottom–Up Strategy

Processes ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 935
Author(s):  
Theresa Schmidt ◽  
Yu Xiang ◽  
Xujin Bao ◽  
Tao Sun
Keyword(s):  
Tissue Engineering ◽  
Cell Types ◽  
Clinical Applications ◽  
Organ Shortage ◽  
Top Down ◽  
Bottom Up ◽  
Multiple Cell ◽  
Size And Morphology ◽  
Modular Scaffolds

Tissue engineering (TE) was initially designed to tackle clinical organ shortage problems. Although some engineered tissues have been successfully used for non-clinical applications, very few (e.g., reconstructed human skin) have been used for clinical purposes. As the current TE approach has not achieved much success regarding more broad and general clinical applications, organ shortage still remains a challenging issue. This very limited clinical application of TE can be attributed to the constraints in manufacturing fully functional tissues via the traditional top–down approach, where very limited cell types are seeded and cultured in scaffolds with equivalent sizes and morphologies as the target tissues. The newly proposed developmental engineering (DE) strategy towards the manufacture of fully functional tissues utilises a bottom–up approach to mimic developmental biology processes by implementing gradual tissue assembly alongside the growth of multiple cell types in modular scaffolds. This approach may overcome the constraints of the traditional top–down strategy as it can imitate in vivo-like tissue development processes. However, several essential issues must be considered, and more mechanistic insights of the fundamental, underpinning biological processes, such as cell–cell and cell–material interactions, are necessary. The aim of this review is to firstly introduce and compare the number of cell types, the size and morphology of the scaffolds, and the generic tissue reconstruction procedures utilised in the top–down and the bottom–up strategies; then, it will analyse their advantages, disadvantages, and challenges; and finally, it will briefly discuss the possible technologies that may overcome some of the inherent limitations of the bottom–up strategy.

ADVANCED TISSUE ENGINEERING STRATEGIES FOR VASCULARIZED PARENCHYMAL CONSTRUCTS

2014 ◽  
Vol 14 (01) ◽  
pp. 1430001 ◽  
Author(s):  
JIANKANG HE ◽  
FENG XU ◽  
YAXIONG LIU ◽  
ZHONGMIN JIN ◽  
DICHEN LI
Keyword(s):  
Tissue Engineering ◽  
Cell Types ◽  
Great Promise ◽  
Top Down ◽  
Bottom Up ◽  
Organ Specific ◽  
Recent Developments ◽  
Multiple Cell ◽  
Complex Structural

The fabrication of vascularized parenchymal organs to alleviate donor shortage in organ transplantation is the holy grail of tissue engineering. However, conventional tissue-engineering strategies have encountered huge challenges in recapitulating complex structural organization of native organs (e.g., orderly arrangement of multiple cell types and vascular network), which plays an important role in engineering functional vascularized parenchymal constructs in vitro. Recent developments of various advanced tissue-engineering strategies have exhibited great promise in replicating organ-specific architectures into artificial constructs. Here, we review the recent advances in top-down and bottom-up strategies for the fabrication of vascularized parenchymal constructs. We highlight the fabrication of microfluidic scaffolds potential for nutrient transport or vascularization as well as the controlled multicellular arrangement. The advantages as well as the limitations associated with these strategies will be discussed. It is envisioned that the combination of microfluidic concept in top-down strategies and multicellular arrangement concept in bottom-up strategies could potentially generate new insights for the fabrication of vascularized parenchymal organs.

scholarly journals Complementary networks of cortical somatostatin interneurons enforce layer specific control

2018 ◽  
Author(s):  
Alexander Naka ◽  
Julia Veit ◽  
Ben Shababo ◽  
Rebecca K. Chance ◽  
Davide Risso ◽  
...  
Keyword(s):  
Transcriptional Profiling ◽  
Neuronal Cell ◽  
Gain Control ◽  
Pyramidal Cells ◽  
Cell Types ◽  
Top Down ◽  
Bottom Up ◽  
Sensory Data ◽  
Layer 4

AbstractThe neocortex is organized into discrete layers of excitatory neurons: layer 4 receives the densest ‘bottom up’ projection carrying external sensory data, while layers 2/3 and 5 receive ‘top down’ inputs from higher cortical areas that may convey sensory expectations and behavioral goals. A subset of cortical somatostatin (SST) neurons gate top down input and control sensory computation by inhibiting the apical dendrites of pyramidal cells in layers 2/3 and 5. However, it is unknown whether an analogous inhibitory mechanism separately and specifically controls activity in layer 4. We hypothesized that distinct SST circuits might exist to inhibit specific cortical layers. By enforcing layer-specific inhibition, distinct SST subnetworks could mediate pathway-specific gain control, such as regulating the balance between bottom up and top down input. Employing a combination of high precision circuit mapping, in vivo optogenetic perturbations, and single cell transcriptional profiling, we reveal distinct and complementary SST circuits that specifically and reciprocally interconnect with excitatory cells in either layer 4 or layers 2/3 and 5. Our data further define a transcriptionally distinct SST neuronal sub-class that powerfully gates bottom up sensory activity during active sensation by regulating layer 4 activity. This integrated paradigm further represents a potentially generalizable approach to identify and characterize neuronal cell types and reveal their in vivo function.

scholarly journals MyD88 Is Not Required for Muscle Injury-Induced Endochondral Heterotopic Ossification in a Mouse Model of Fibrodysplasia Ossificans Progressiva

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 630
Author(s):  
Huili Lyu ◽  
Cody M. Elkins ◽  
Jessica L. Pierce ◽  
C. Henrique Serezani ◽  
Daniel S. Perrien
Keyword(s):  
Heterotopic Ossification ◽  
Muscle Injury ◽  
Cell Types ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Inflammatory Signaling ◽  
Conditional Deletion ◽  
Pathway Crosstalk ◽  
Multiple Cell

Excess inflammation and canonical BMP receptor (BMPR) signaling are coinciding hallmarks of the early stages of injury-induced endochondral heterotopic ossification (EHO), especially in the rare genetic disease fibrodysplasia ossificans progressiva (FOP). Multiple inflammatory signaling pathways can synergistically enhance BMP-induced Smad1/5/8 activity in multiple cell types, suggesting the importance of pathway crosstalk in EHO and FOP. Toll-like receptors (TLRs) and IL-1 receptors mediate many of the earliest injury-induced inflammatory signals largely via MyD88-dependent pathways. Thus, the hypothesis that MyD88-dependent signaling is required for EHO was tested in vitro and in vivo using global or Pdgfrα-conditional deletion of MyD88 in FOP mice. As expected, IL-1β or LPS synergistically increased Activin A (ActA)-induced phosphorylation of Smad 1/5 in fibroadipoprogenitors (FAPs) expressing Alk2R206H. However, conditional deletion of MyD88 in Pdgfrα-positive cells of FOP mice did not significantly alter the amount of muscle injury-induced EHO. Even more surprisingly, injury-induced EHO was not significantly affected by global deletion of MyD88. These studies demonstrate that MyD88-dependent signaling is dispensable for injury-induced EHO in FOP mice.

scholarly journals Single-cell mapping of focused ultrasound-transfected brain

Gene Therapy ◽  
2021 ◽  
Author(s):  
A. S. Mathew ◽  
C. M. Gorick ◽  
R. J. Price
Keyword(s):  
Single Cell ◽  
Focused Ultrasound ◽  
Cell Types ◽  
Brain Cell ◽  
Therapeutic Modality ◽  
Full Potential ◽  
Stress Genes ◽  
Multiple Cell ◽  
Differential Gene

AbstractGene delivery via focused ultrasound (FUS) mediated blood-brain barrier (BBB) opening is a disruptive therapeutic modality. Unlocking its full potential will require an understanding of how FUS parameters (e.g., peak-negative pressure (PNP)) affect transfected cell populations. Following plasmid (mRuby) delivery across the BBB with 1 MHz FUS, we used single-cell RNA-sequencing to ascertain that distributions of transfected cell types were highly dependent on PNP. Cells of the BBB (i.e., endothelial cells, pericytes, and astrocytes) were enriched at 0.2 MPa PNP, while transfection of cells distal to the BBB (i.e., neurons, oligodendrocytes, and microglia) was augmented at 0.4 MPa PNP. PNP-dependent differential gene expression was observed for multiple cell types. Cell stress genes were upregulated proportional to PNP, independent of cell type. Our results underscore how FUS may be tuned to bias transfection toward specific brain cell types in vivo and predict how those cells will respond to transfection.

scholarly journals Production of Human Pluripotent Stem Cell-Derived Hepatic Cell Lineages and Liver Organoids: Current Status and Potential Applications

2020 ◽  
Vol 7 (2) ◽  
pp. 36 ◽  
Author(s):  
João P. Cotovio ◽  
Tiago G. Fernandes
Keyword(s):  
Cell Types ◽  
In Vitro Models ◽  
Hepatic Cell ◽  
Current Status ◽  
Organ Shortage ◽  
Cell Lineages ◽  
Potential Applications ◽  
Liver Organoids

Liver disease is one of the leading causes of death worldwide, leading to the death of approximately 2 million people per year. Current therapies include orthotopic liver transplantation, however, donor organ shortage remains a great challenge. In addition, the development of novel therapeutics has been limited due to the lack of in vitro models that mimic in vivo liver physiology. Accordingly, hepatic cell lineages derived from human pluripotent stem cells (hPSCs) represent a promising cell source for liver cell therapy, disease modelling, and drug discovery. Moreover, the development of new culture systems bringing together the multiple liver-specific hepatic cell types triggered the development of hPSC-derived liver organoids. Therefore, these human liver-based platforms hold great potential for clinical applications. In this review, the production of the different hepatic cell lineages from hPSCs, including hepatocytes, as well as the emerging strategies to generate hPSC-derived liver organoids will be assessed, while current biomedical applications will be highlighted.

scholarly journals Regulation of Fertility, Survival, and Cuticle Collagen Function by the Caenorhabditis elegans eaf-1 and ell-1 Genes

2011 ◽  
Vol 286 (41) ◽  
pp. 35915-35921 ◽  
Author(s):  
Liquan Cai ◽  
Binh L. Phong ◽  
Alfred L. Fisher ◽  
Zhou Wang
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Types ◽  
Transcriptional Elongation ◽  
Human Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Transcription Factor Family ◽  
Collagen Expression ◽  
Extracellular Matrix Components ◽  
Multiple Cell

EAF2, an androgen-regulated protein, interacts with members of the ELL (eleven-nineteen lysine-rich leukemia) transcription factor family and also acts as a tumor suppressor. Although these proteins control transcriptional elongation and perhaps modulate the effects of other transcription factors, the mechanisms of their actions remain largely unknown. To gain new insights into the biology of the EAF2 and ELL family proteins, we used Caenorhabditis elegans as a model to explore the in vivo roles of their worm orthologs. Through the use of transgenic worms, RNAi, and an eaf-1 mutant, we found that both genes are expressed in multiple cell types throughout the worm life cycle and that they play important roles in fertility, survival, and body size regulation. ELL-1 and EAF-1 likely contribute to these activities in part through modulating cuticle synthesis, given that we observed a disrupted cuticle structure in ell-1 RNAi-treated or eaf-1 mutant worms. Consistent with disruption of cuticle structure, loss of either ELL-1 or EAF-1 suppressed the rol phenotype of specific collagen mutants, possibly through the control of dpy-3, dpy-13, and sqt-3 collagen gene expression. Furthermore, we also noted the regulation of collagen expression by ELL overexpression in PC3 human prostate cancer cells. Together, these results reveal important roles for the eaf-1 and ell-1 genes in the regulation of extracellular matrix components.

Wnt5a Promotes Lysosomal Cholesterol Egress and Protects Against Atherosclerosis

2021 ◽  
Author(s):  
Sara Awan ◽  
Magalie Lambert ◽  
Ali Imtiaz ◽  
Fabien Alpy ◽  
Catherine Tomasetto ◽  
...  
Keyword(s):  
Dietary Cholesterol ◽  
Cell Types ◽  
Cholesterol Content ◽  
Cholesterol Homeostasis ◽  
Cholesterol Trafficking ◽  
Atherosclerotic Lesions ◽  
Crucial Component ◽  
Multiple Cell ◽  
Niemann Pick

Background: Impairment of cellular cholesterol trafficking is at the heart of atherosclerotic lesions formation. This involves egress of cholesterol from the lysosomes and two lysosomal proteins, the Niemann-Pick C1 (NPC1) and NPC2 that promotes cholesterol trafficking. However, movement of cholesterol out the lysosome and how disrupted cholesterol trafficking leads to atherosclerosis is unclear. As the Wnt ligand, Wnt5a inhibits the intracellular accumulation of cholesterol in multiple cell types, we tested whether Wnt5a interacts with the lysosomal cholesterol export machinery and studied its role in atherosclerotic lesions formation. Methods: We generated mice deleted for the Wnt5a gene in vascular smooth muscle cells (VSMCs). To establish whether Wnt5a also protects against cholesterol accumulation in human VSMCs, we used a CRISPR/Cas9 guided nuclease approach to generate human VSMCs knockout for Wnt5a. Results: We show that Wnt5a is a crucial component of the lysosomal cholesterol export machinery. By increasing lysosomal acid lipase expression, decreasing metabolic signaling by the mTORC1 kinase, and through binding to NPC1 and NPC2, Wnt5a senses changes in dietary cholesterol supply and promotes lysosomal cholesterol egress to the endoplasmic reticulum (ER). Consequently, loss of Wnt5a decoupled mTORC1 from variations in lysosomal sterol levels, disrupted lysosomal function, decreased cholesterol content in the ER, and promoted atherosclerosis. Conclusions: These results reveal an unexpected function of the Wnt5a pathway as essential for maintaining cholesterol homeostasis in vivo.

Tough Double-Network Hydrogels as Scaffolds for Tissue Engineering

2012 ◽  
pp. 213-222
Author(s):  
Jing Jing Yang ◽  
Jian Fang Liu ◽  
Takayuki Kurokawa ◽  
Nobuto Kitamura ◽  
Kazunori Yasuda ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Three Dimensional ◽  
Cartilage Regeneration ◽  
Cell Types ◽  
Embryoid Bodies ◽  
Living Tissue ◽  
Double Network ◽  
Dimensional Network

Hydrogels are used as scaffolds for tissue engineering in vitro & in vivo because their three-dimensional network structure and viscoelasticity are similar to those of the macromolecular-based extracellular matrix (ECM) in living tissue. Especially, the synthetic hydrogels with controllable and reproducible properties were used as scaffolds to study the behaviors of cells in vitro and implanted test in vivo. In this review, two different structurally designed hydrogels, single-network (SN) hydrogels and double-network (DN) hydrogels, were used as scaffolds. The behavior of two cell types, anchorage-dependent cells and anchorage-independent cells, and the differentiation behaviors of embryoid bodies (EBs) were investigated on these hydrogels. Furthermore, the behavior of chondrocytes on DN hydrogels in vitro and the spontaneous cartilage regeneration induced by DN hydrogels in vivo was examined.

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