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Studies of cell fate focus on specification, but little is known about maintenance of the differentiated state. In this study, we find that the mouse tendon cell fate requires continuous maintenance in vivo and identify an essential role for TGFβ signaling in maintenance of the tendon cell fate. To examine the role of TGFβ signaling in tenocyte function the TGFβ type II receptor (Tgfbr2) was targeted in the Scleraxis-expressing cell lineage using the ScxCre deletor. Tendon development was not disrupted in mutant embryos, but shortly after birth tenocytes lost differentiation markers and reverted to a more stem/progenitor state. Viral reintroduction of Tgfbr2 to mutants prevented and even rescued tenocyte dedifferentiation suggesting a continuous and cell autonomous role for TGFβ signaling in cell fate maintenance. These results uncover the critical importance of molecular pathways that maintain the differentiated cell fate and a key role for TGFβ signaling in these processes.

Studies of cell fate focus on specification, but little is known about maintenance of the differentiated state. In this study, we find that the mouse tendon cell fate requires continuous maintenance in vivo and identify an essential role for TGF[beta] signaling in maintenance of the tendon cell fate. To examine the role of TGF[beta] signaling in tenocyte function the TGF[beta] type II receptor (Tgfbr2) was targeted in the Scleraxis-expressing cell lineage using the ScxCre deletor. Tendon development was not disrupted in mutant embryos, but shortly after birth tenocytes lost differentiation markers and reverted to a more stem/progenitor state. Viral reintroduction of Tgfbr2 to mutants prevented and even rescued tenocyte dedifferentiation suggesting a continuous and cell autonomous role for TGF[beta] signaling in cell fate maintenance. These results uncover the critical importance of molecular pathways that maintain the differentiated cell fate and a key role for TGF[beta] signaling in these processes.

Abstract Understanding the role of cell recruitment in tendon disorders is critical for improvements in regenerative therapy. We recently reported that targeted disruption of TGFβ type II receptor in the tendon cell lineage (Tgfbr2ScxCre) resulted in tenocyte dedifferentiation and tendon degradation in post-natal stages. Here we extend the analysis and identify direct recruitment of stem/progenitor cells into the degenerative mutant tendons. Cre-lineage tracing indicates that these cells are not derived from tendon ensheathing tissues or from a Scleraxis-lineage, and they turned on tendon markers only upon entering the mutant tendons. Through immunohistochemistry and inducible gene deletion, we further find that the recruited cells originated from a Sox9-expressing lineage and their recruitment was dependent on cell-autonomous TGFβ signaling. These results thus differ from previous reports of cell recruitment into injured tendons, and suggest a critical role for TGFβ signaling and cell recruitment in the etiology and treatment of tendon degeneration. Competing Interest Statement The authors have declared no competing interest.

Attachment sites of tendons to bones, called entheses, are essential for proper musculoskeletal function. They are formed embryonically by Sox9+ progenitors and undergo a developmental process that continues into the postnatal period and involves Gli1 lineage cells. During bone elongation, some entheses maintain their relative positions by actively migrating along the bone shaft, while others, located at the bone's extremities, remain stationary. Despite their importance, we lack information on the developmental transition from embryonic to mature enthesis and on the relation between Sox9+ progenitors and Gli1 lineage cells. Here, by performing a series of lineage tracing experiments, we identify the onset of Gli1 lineage contribution to different entheses during embryogenesis. We show that Gli1 expression is regulated by SHH signaling during embryonic development, whereas postnatally it is maintained by IHH signaling. Interestingly, we found that unlike in stationary entheses, where Sox9+ cells differentiate into the Gli1 lineage, in migrating entheses the Sox9 lineage is replaced by Gli1 lineage and do not contribute to the mature enthesis. Moreover, we show that these Gli1+ progenitors are pre-specified embryonically to form the different cellular domains of the mature enthesis. Overall, these findings demonstrate a developmental strategy whereby one progenitor population establishes a simple, embryonic tissue, whereas another population is responsible for its maturation into a complex structure during its migration. Moreover, they suggest that different cell populations may be considered for cell-based therapy of enthesis injuries.

Studies of cell fate focus on specification, but little is known about maintenance of the differentiated state. We find that TGFβ signaling plays an essential role in maintenance of the tendon cell fate. To examine the role TGFβ signaling in tenocytes TGFb type II receptor was targeted in the Scleraxis cell lineage. Tendon development was not disrupted in mutant embryos, but shortly after birth tenocytes lost differentiation markers and reverted to a more stem/progenitor state. Targeting of Tgfbr2 using other Cre drivers did not cause tenocyte dedifferentiation suggesting a critical significance for the spatio-temporal activity of ScxCre. Viral reintroduction of Tgfbr2 to mutants was sufficient to prevent and even rescue mutant tenocytes suggesting a continuous and cell-autonomous role for TGFβ signaling in cell fate maintenance. These results uncover the critical importance of molecular pathways that maintain the differentiated cell fate and a key role for TGFβ signaling in these processes.

Coordinated development of muscles, tendons, and their attachment sites ensures emergence of functional musculoskeletal units that are adapted to diverse anatomical demands among different species. How these different tissues are patterned and functionally assembled during embryogenesis is poorly understood. Here, we investigated the morphogenesis of extraocular muscles (EOMs), an evolutionary conserved cranial muscle group that is crucial for the coordinated movement of the eyeballs and for visual acuity. By means of lineage analysis, we redefined the cellular origins of periocular connective tissues interacting with the EOMs, which do not arise exclusively from neural crest mesenchyme as previously thought. Using 3D imaging approaches, we established an integrative blueprint for the EOM functional unit. By doing so, we identified a developmental time window in which individual EOMs emerge from a unique muscle anlage and establish insertions in the sclera, which sets these muscles apart from classical muscle-to-bone type of insertions. Further, we demonstrate that the eyeballs are a source of diffusible all-trans retinoic acid (ATRA) that allow their targeting by the EOMs in a temporal and dose-dependent manner. Using genetically modified mice and inhibitor treatments, we find that endogenous local variations in the concentration of retinoids contribute to the establishment of tendon condensations and attachment sites that precede the initiation of muscle patterning. Collectively, our results highlight how global and site-specific programs are deployed for the assembly of muscle functional units with precise definition of muscle shapes and topographical wiring of their tendon attachments.

BackgroundThe effectiveness of tax increases relies heavily on the tobacco industry passing on such increases to smokers (also referred to as ‘pass-through’). Previous research has found heterogeneous levels of tax pass-through across the market segments of tobacco products available to smokers. This study uses retail sales data to assess the extent to which recent tax changes have been passed on to smokers and whether this varies across the price distribution.MethodsWe use panel data quantile regression analysis on Nielsen commercial data of tobacco price and sales in the UK from January 2013 to March 2019 combined with official UK tax rates and inflation to calculate the rate of tax pass-through for factory made (FM) cigarettes and roll your own (RYO) tobacco.ResultsFollowing increases in the specific tax payable on tobacco, we find evidence of overshifting across the price distribution for both FM and RYO. The rate of the overshift in tax increased the more expensive the products were. This was consistent for FM and RYO. Additionally, our findings suggest that the introduction of standardised packaging was not followed by changes in how the tobacco industry responded to tax increases.ConclusionsFollowing the repeated introduction of increases in specific tobacco tax as well as standardised packaging, we show that the tobacco industry applies techniques to keep the cheapest tobacco cheaper relative to the more expensive products when passing on tax increases to smokers.

Justin Rubio and colleagues report results of a genome-wide association study of multiple sclerosis using cases from Australia and New Zealand. Their findings confirm several published risk loci for MS and identify two new risk loci on chromosomes 12 and 20. To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13–14 (rs703842, P = 5.4 × 10 −11 ; rs10876994, P = 2.7 × 10 −10 ; rs12368653, P = 1.0 × 10 −7 ) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 × 10 −7 ; rs1569723, P = 2.9 × 10 −7 ). Both loci are also associated with other autoimmune diseases 1 , 2 , 3 , 4 , 5 . We also replicated several known MS associations (HLA-DR15, P = 7.0 × 10 −184 ; CD58 , P = 9.6 × 10 −8 ; EVI5-RPL5 , P = 2.5 × 10 −6 ; IL2RA , P = 7.4 × 10 −6 ; CLEC16A , P = 1.1 × 10 −4 ; IL7R , P = 1.3 × 10 −3 ; TYK2 , P = 3.5 × 10 −3 ) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 ( P = 0.001).

Background Cardiovascular disease (CVD) risks are of concern among immigrants and refugees settling in affluent host countries. The prevalence of CVD and risk factors among Somali African immigrants to the U.S. has not been systematically studied. Methods In 2015–2016, we surveyed 1156 adult Somalis in a Midwestern metropolitan area using respondent-driven sampling to obtain anthropometric, interview, and laboratory data about CVD and associated risk factors, demographics, and social factors. Results The prevalence of diabetes and low physical activity among men and women was high. Overweight, obesity, and dyslipidemia were also particularly prevalent. Levels of calculated CVD risk across the community were greater for men than women. Conclusion Though CVD risk is lower among Somalis than the general U.S. population, our results suggest significant prevalence of risk factors among Somali immigrants. Comparison with prior research suggests that CVD risks may be increasing, necessitating thoughtful intervention to prevent adverse population outcomes.