1.     Dermal Adipocyte Lipolysis and Myofibroblast Conversion Are Required for Efficient Skin Repair (Shook et al., 2020; Cell Stem Cell)

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This paper from a group at Yale investigated into the role of lipolysis in adipocytes of the skin stroma in skin wound healing. They first observed that adipocytes are needed for skin wound healing by destroying adipocytes in mice. These mice then showed reduction in re-vascularization and re-epithelialization in the skin wounds. They then showed that during skin injury, adipocytes undergo lipolysis i.e. break down of lipids into fatty acids. Turns out, this lipolysis initiation is critical for the recruitment of immune cells monocytes and/or  macrophages to the site of injury.

 

Next, the authors also noted that after injury-induced lipolysis, these adipocytes do not refill with lipids. Via the use of single-cell RNA sequencing, the authors found that these adipocytes loses their adipogenic identity and becomes myofibroblast to support skin repair by producing extracellular matrix proteins.

 

These findings are super exciting because it shows a relationship between lipolysis in adipocytes, inflammation responses and skin repair; and during this process, the adipocytes ‘dedifferentiate’ and adopt a different cellular identity. This shows that the adipocytes have tremendous cellular plasticity which were initiated by injury signals. This study definitely has help better understand skin wound healing.

 

2.     Genome-Wide Association Study Identifies Genetic Associations with Perceived Age (Roberts et al., 2020; J Investigative Dermatology)

 

This interesting paper aims to uncover genetic factors associated with perceived age by using Genome-Wide Association Study (GWAS). This study was performed in the UK and had a sample size of more than 400,000 participants. The authors’ goal was to identify genetic mechanisms underlying dermal integrity and photoprotective mechanisms of the skin which influences perceived age. First, participants were asked to report if they looked their age, older than their age or younger than their age. Then their DNA were sequences and compared. The authors identified 74 new genetic loci which were associated with perceived age.

 

Of the 74, the strongest statistical evidence was seen at loci C9orf66-DOCK8. Within this loci, rs139356332_G, an uncommon intronic variant within MFAP4 was observed to increase odds of participants reporting that they looked older than their age. MFAP4 gene encodes for am extracellular glycoprotein that is thought to be involved in extracellular matrix organization.

 

Also, the authors were able to corroborate other studies wherein rs12203592_C, a common intronic variant within IRF4 was observed to increase the odds of participants reporting that they looked younger than their age. Interestingly, the authors showed via gene enrichment analysis that obesity-related traits were correlated with perceived age i.e. genotypes associated with greater adiposity (more fat tissue content) overlapped with genotypes associated with reduced odds of appearing younger than age. 

 

Overall, the authors were able to conclude that apparent age is partially heritable. These interesting findings will prove to be useful in better understanding skin biology, aging and finding interventions to tackle age-related skin changes.

 

3.     Soft Matrix Promotes Cardiac Reprogramming via Inhibition of YAP/TAZ and Suppression of Fibroblast Signatures (Kurotsu et al., 2020; Stem Cell Reports)

 

The authors presented an innovative method to increase the efficiency of direct reprogramming of fibroblasts to cardiomyocytes (induced cardiomyocytes; iCMs) and the quality of those iCMs. Other previously published studies on deriving induced cardiomyocytes were done on conventional cell culture dishes (made form plastic) and/or coated with commercial Matrigel. Instead, the authors seeded a layer of fibroblasts on Matrigel-based hydrogels of varying stiffness before reprogramming them.They found that soft substrates (4-14kPa) resulted in significantly higher number of beating cardiomyocytes, especially the substrate with 8kPa of stiffness. In addition, the contraction/ relaxation velocities of iCMs on 8kPa hydrogels were higher than other stiffer substrates which is indicative of functionally mature cardiomyocytes.

 

The authors also reported higher expression of Hcn4, which marks for pacemaker cells, in the iCMs. FACs analyses confirmed that 8kPa hydrogels induced more cardiac troponin T (cTNT) cells. Lastly, the iCMs showed more well-developed sarcomeric structures. Overall, the 8kPa hydrogel tremendously improved reprogramming efficiency and increased maturity and functionality of the iCMs.The authors then proceeded on to understand the underlying mechanism to this observation. They performed microarray analyses and uncovered that iCMs grown on 8kPa hydrogels upregulated genes associated with cardiac function and downregulation of fibroblast signatures. They then revealed that YAP/TAZ signaling was suppressed which resulted in the promotion of cardiac reprogramming and repression of fibroblast genes.

 

In summary, the authors were able to improve current methods of reprogramming fibroblasts to cardiomyocytes using a softer form of Matrigel-based hydrogel which prompts us to think about the types of gels/ plates we typically use during cell culture or even stem cell differentiation and how that influences both differentiation efficiencies and later on the maturity and functionality of the cells.

1. Single-cell RNA-sequencing reveals distinct patterns of cell state heterogeneity in mouse models of breast cancer (Yeo et al., 2020) 

 

The authors utilized single-cell RNA sequencing technology to find out more about the heterogeneity within mammary tumours which are tumours of the mammary gland located at the breast tumour cells. They performed single-cell RNA sequencing on tumour cells obtained from different mouse models of breast cancer. 

 

First, they showed that tumour cells from the three different breast cancer mouse models Neu, PyMT and BRCA1-null were all distinctively different (at a single-cell resolution) consistent with the fact that all three different models were caused by different oncogenic mechanisms. Next, they compared the tumour cells with normal mouse mammary epithelial cells across different developmental stages and found that different tumour cells (different models) correspond to different differentiation states of the mammary gland (on a spectrum of cell states) and also suggest potential lineage-specificities of these cells. 

 

Within individual tumours (of each model), tumour cells are also highly diverse. For instance, the authors revealed that in the tumour cells in Neu tumours can be classified into 4 clusters. One of the clusters show an upregulation of CD14, which is a luminal progenitor maker. The authors were able to isolate Neu tumour cells expressing high levels of CD14 from the Neu tumours and transplanted them into mice. Afterwhich, they showed that a small number of these cells were able to form tumours in these mice (as compared to Neu tumour cells expressing low levels of CD14. 

 

Overall, although this this paper is highly descriptive, it will be a valuable resource for. future in-depth studies into tumour cell heterogeneity, isolate specific tumour cells to better understand how individuals tumour cells can contribute to tumorigenesis in different breast cancer models.  

 

2.     Intrinsic Endocardial Defects Contribute to Hypoplastic Left Heart Syndrome (Miao et al., 2020)

 

Here is another paper utilizing the powerful single-cell RNA sequencing technology but this time to understand more about the etiology of hypoplastic left heart syndrome (HLHS). HLHS is a severe congenital heart disease characterized by various forms of heart malformations wherein the left side of the heart is critically underdeveloped. HLHS is a developmental disorder and therefore affects newborns.

 

The authors obtained HLHS patient iPSCs and differentiate them to a heterogenous pool of endothelial cells (ECs) using a published protocol. Single-cell RNA sequencing of HLHS iPSC-derived ECs revealed a reduction in expression of endocardial genes (as compared to control ECs) which corresponds to low endocardial gene/ protein expression in HLHS patient heart tissues. The data also showed suppression of pathways related to endocardial functions. One of such pathways is extracellular matrix (ECM) deposition which is important for development of vascular structures and another pathway, NOTCH signaling is important for valvular development (development of heart valves).

 

The authors also performed an interesting experiment where they co-cultured HLHS-ECs. with normal iPSC-derived cardiomyocytes (CM) and found that the CM developed dysfunctions such as decreased contractile functions, disruption in sarcomeric structures and reduced maturation. This provides evidence to suggest that HLHS endocardium negatively influence myocardial development in a profound manner.In addition, they compared the sc-RNA seq data with sc-RNA seq data of underdeveloped left ventricle of human fetal hearts and discovered that expression of Fribonectin 1 (FN1) was downregulated in both samples. When FN1 was knocked down in normal iPSC-ECs and co-cultured with iPSC-CM, iPSC-CM displayed dysfunctional phenotype similar to when cultured with HLHS-ECs. This collectively indicates that the endocardium is involved in cardiac development and that development process was dysregulated in HLHS.

 

In conclusion, this paper provided novel insights into the molecular pathogenesis of HLHS with the use of patient iPSCs and advance single-cell technology. They even co-cultured ECs and CMs to delineate the relationship between both during heart development. This paper also compared and integrated data sets of human fetal tissues with provides strong evidences for their findings.

1. Axonal Extensions along Corticospinal Tracts from Transplanted Human Cerebral Organoids (Kitahara et al., 2020; Stem Cell Reports)

 

The authors aimed to optimize the methodology of transplanting cerebral organoids differentiated from human embryonic stem cells to treat cerebral cortex injuries caused by brain injuries or even stroke. They utilized a previously-published protocol to obtain cerebral organoids that were able to accurately mimic the cerebral cortical developmental process.

 

After 6 weeks, they were able to get an ‘early-stage’ organoid which has formed subcerebral projection neurons (SCPNs), which in the brain extend axons outside of the cerebral cortex. After 10 weeks, they were able to get a ‘late-stage’ organoid which are composed by callosal projection neurons (CPNs), which in the brain extends axons to other areas of the cerebral cortex. They transplanted both 6 weeks (6w) and 10 weeks-old (10w) organoids into mice and were able to see the extension of large numbers of axons along the host corticospinal tract. Although 6w organoids were able to form more axon extensions, they also contained more proliferative cells and resulted in graft over-growth after transplantation into injured adult mice brain.

 

This study has provided great promise for the use of cerebral organoids to reconstruct injured motor pathways in individuals suffering from brain injuries or even stroke.

 

2. Zonation of Pancreatic Acinar Cells in Diabetic Mice (Egozi et al., 2020; Cell Reports)

 

This interesting paper drew inspiration from the concept of zonation in liver. In brief, the hepatocytes (liver cells) in the liver are highly heterogenous and are segregated based on their proximity to main vessels in the liver i.e. periportal vein and central vein. This is also known as liver zonation. The authors sought to explore if acinar cells of the pancreas adopt a similar zonation pattern based on their proximity to pancreatic islets -‘peri-islet’ acinar cells are spatially close to the islet while ‘tele-islet’ acinar cells are father away.

 

This study provided new insights into the zonation of pancreatic acinar cells especially in the context of diabetes. They found that peri-islet acinar cells expressed higher levels of trypsin genes than tele-islet acinar cells in diabetic mice. Trypsin genes comprises of genes encoding for serine proteases. This acinar zonation profile seem to be regulated by islet hormone which encodes for intestinal entero-endocrine hormone cholecystokinin instead of insulin. This is interesting given that peri-islet acinar cells are exposed to higher levels of insulin (that are produced by beta cells of the islets).

 

Next, the authors also found that mTOR signaling is zonated in the acinar cells i.e. higher levels in peri-islet acinar cells of diabetic mice. mTOR is known to be activated by therefore supporting the theory of -driven acinar zonation. Finally, to support their findings, the authors looked at acinar zonation in older mice and noted a decline in acinar zonation profile, which correlated with decreased levels of .

 

It would be valuable for future studies to explore the functional role(s) of acinar profile and how that is altered during diabetes. It will also be interesting to see how acinar zonation came about during pancreatic development.

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3. In Situ Expansion, Differentiation, and Electromechanical Coupling of Human Cardiac Muscle in a 3D Bioprinted, Chambered Organoid (Kupfer et al., 2020; Circulation Research)

 

This amazing tissue engineering paper describes a method to 3D bio-print functional, chambered cardiac organoids (heart organoids) composed of heart muscle cell known as cardiomyocytes. The group also formulated their own bioink that is able to enable stem cell proliferation and subsequent differentiation into cardiomyocytes and is able to be printed into complex structures.

 

What’s really cool is that the 3D organoid is designed to mimic the heart – septum between ventricles and two vessel-like extrusions extending from the top of the organoid corresponding to the aorta and vena cava. These ‘vessels’ could be attached to a perfusion platform.

 

To summarize, the stem cells that were bioprinted into the organoid were able to differentiate into cardiomyocyte to form a muscle wall, creating a human chambered muscle pumps (hChaMPs) as termed by the authors. hChaMPs exhibited mature cardiomyocyte phenotypes such as profound sarcomeric organization. hChaMPs also are tested to have electromechanical functions and have pumping capacity/ functionality similar to a mouse heart.

 

This paper highlights the technological advances in 3D bio-printing and being able to produce a 3D printed chambered, pumping heart structure will revolutionize disease modeling, drug testing and pre-clinical therapy in the near future.