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Human skeletal muscle CD90+ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients

Jean Farup, Jesper Just, Frank de Paoli, Lin Lin, Jonas Brorson Jensen, Tine Billeskov, Ines Sanchez Roman, Cagla Cömert, Andreas Buch Møller, Luca Madaro, Elena Groppa, Rikard Göran Fred, Ulla Kampmann, Steen B. Pedersen, Peter Bross, Tinna Stevnsner, Nikolaj Eldrup, Tune H. Pers, Fabio M. V. Rossi, Pier Lorenzo Puri, Niels Jessen

Posted on: 10 September 2020 , updated on: 16 September 2020

Preprint posted on 25 August 2020

Article now published in Cell Metabolism at http://dx.doi.org/10.1016/j.cmet.2021.10.001

Human skeletal muscle fibro-adipogenic remodelling and degeneration in type 2 diabetes

Selected by Osvaldo Contreras, Nicolas Collao

Background

Obesity and obesity-related disorders are a global epidemic (for review see Blüher, 2019). People with obesity have increased risk of morbidity and mortality mainly due to comorbidities associated with excessive weight gain, hyperglycemia and metabolic impairment (Piché et al., 2020). Therefore, obesity negatively impacts the quality of life of obese individuals and represents a major burden on our ageing society. Type 2 diabetes (T2D) is a progressive condition and the risk of developing T2D dramatically increases with obesity, insufficient physical activity and ageing. In T2D our cells become resistant to the effects of insulin (a peptide hormone which reduces the levels of glucose in the blood) and/or the pancreas loses its competence to produce insulin, which results in hyperglycemia. Additionally, obese individuals with T2D develop muscle atrophy – a condition where muscles are smaller than normal – and fibro-fatty infiltration, both of which negatively affect muscle contractile function (Hilton et al., 2008; Tam et al., 2014).

The adult mammalian skeletal muscles are composed of many cell types, and therefore their niche composition is highly complex and dynamic, especially upon damage. Muscle cells communicate by physically interacting and/or secreting a plethora of factors to maintain muscle homeostasis. When muscle homeostasis is acutely disrupted following injury, adult muscle stem cells (MuSCs) (also known as satellite cells) activate, proliferate, self-renew, and differentiate to fuse with pre-existent myofibers to effectively restore the lost muscle to its previous condition, a phenomenon called adult skeletal muscle regeneration (Joe et al., 2010). However, during chronic degenerative conditions, such as obesity, T2D, and ageing, the muscle milieu is gradually disrupted, leading to a pathophysiological condition that triggers exacerbated accumulation of extracellular matrix (ECM) and adipose tissue. This associates with muscle metabolic profile dysregulation, increased tissue stiffness and reduced contraction of the affected muscles (Buras et al., 2019; Collao et al., 2020; Teng et al., 2019). Fibro-adipogenic progenitors (FAPs) are the fibroblasts of mammalian muscles with multipotency towards all the mesenchymal cell lineages (Contreras et al., 2019; Eisner et al., 2020; Kopinke et al., 2017; Scott et al., 2019; Uezumi et al., 2010, 2014). FAPs are diverse and dynamic cells required for adult muscle maintenance and effective muscle regeneration (De Micheli et al., 2020; Giordani et al., 2019; Malecova et al., 2018; Marinkovic et al., 2019; Wosczyna et al., 2019). However, FAPs can contribute to muscle pathology, where chronic injury and inflammation blunt muscle regeneration and lead to progressive tissue degeneration (Contreras et al., 2016; Hogarth et al., 2019; Reggio et al., 2020). Although important progress has been made in understanding the heterogeneity of the stromal compartment in muscle health, regeneration, and disease (Oprescu et al., 2020; Rubenstein et al., 2020; Scott et al., 2019), the cellular and molecular responses of human skeletal muscle FAPs to gradual degenerative diseases are underexplored.

In this preprint, Farup and colleagues unveiled a subpopulation of human muscle-resident FAPs that associates with progressive muscle degeneration in T2D patients. They suggested that a subset of muscle FAPs (LinCD56CD82CD34+CD90+) associates with enhanced fibrosis and ectopic adipose tissue in degenerative T2D settings, shedding new light on the role of fibro-adipogenic progenitors underpinning skeletal muscle degenerative fibro-fatty remodelling in the obese and T2D population.

Obese individuals with T2D develop muscle atrophy – a condition where muscles are smaller than normal – and fibro-fatty infiltration, both of which negatively affect muscle contractile function.

Key findings

First, using skeletal muscle biopsies, the authors profiled bulk transcriptomic changes from 3 separate groups: individuals with obesity, T2D, or insulin-treated T2D (itT2D), which represented a disease progression-type model that associates with the severity of insulin resistance (obese<T2D<itT2D). Farup et al. found increased ECM remodelling gene signatures in itT2D, and therefore, hypothesised that FAPs influence muscle pathology in hyperglycemic patients. To further test this hypothesis, the authors isolated and characterized human FAPs from muscle biopsies based on CD90 cell-surface protein expression using fluorescent-activated cell sorting (FACS). This because neither of the tested antibodies against PDGFRA (also known as CD140a) worked -even when PDGFRA is highly expressed in human FAPs- nor Sca-1/Ly6a antigen is expressed in human cells, which are two well-characterized FAP markers in mouse skeletal muscles. The authors also corroborated that human FAPs display clonal expansion (4% for FAPs compared to 17% for MuSCs) and are distinct to other muscle-resident populations of mononuclear cells, which confirm previous findings in mice. Platelet-derived growth factors (PDGFs) bind to PDGFRα and PDGFRβ to regulate key molecular and cellular processes including proliferation, migration and gene expression. Furthermore, PDGF signaling regulates the fate of skeletal muscle FAPs (Contreras et al., 2019; Mueller et al., 2016). Farup et al. described that PDGFRA expression correlates with COLLAGEN 1A1 expression, as previously proposed (Contreras et al., 2019). Owing to this relationship, they asked whether PDGF signalling could impact the fate of FAPs. PDGF-AA treatment increased the expression of fibrillar collagen in FAPs, whereas it reduced their adipogenic differentiation. The authors showed that the PDGF-AA-mediated fibrogenic activation of FAPs associates with a metabolic switch that favours an enhanced consumption of glucose in these cells compared to non-treated cells. This increased glycolytic flux present in TGF-b-induced fibrogenic conditions seems to be required for enhanced ECM synthesis and deposition by FAPs.

The expression of the cell-surface protein CD90 has been widely used to identify tissue-resident fibroblasts and/or mesenchymal stromal/stem cells in different tissues and organs. In this preprint, combining FACS with single-cell RNA-seq, the authors showed that CD90 expression was restricted to a particular FAPs subpopulation. Remarkably, CD90 positive (CD90+) FAPs and CD90 negative (CD90) FAPs exhibited distinct phenotypic and molecular signatures. CD90+ FAPs were bigger in size, proliferated faster, and displayed higher expression of extracellular matrix genes compared to CD90- FAPs. Glycolytic flux and maximal oxygen consumption were also higher in CD90+ FAPs compared to CD90- FAPs. These results suggest that at least two distinct FAP subpopulations are present in skeletal muscle and are distinguished by the expression of CD90/THY1. Since evidence of fibrosis was detected in skeletal muscle biopsies from patients with T2D, the authors compared the content of the CD90+, pro-fibrotic FAP subpopulation between patients with T2D and healthy controls. They found that the CD90+ FAP subpopulation was higher in muscles of individuals with T2D compared to non-T2D controls. Further, CD90+ FAPs from patients with T2D proliferated faster and had higher expression of COLLAGEN 1 compared to muscleCD90+ FAPs isolated from non-diabetic individuals. And lastly, the authors sought to pharmacologically target FAPs to prevent their excessive accumulation and fibro-fatty infiltration in muscles of T2D patients. Metformin is a usual first-line pharmacological approach to counteract T2D. Metformin treatment reduced the proliferation, oxygen consumption, and adipogenic differentiation of CD90+ FAPs but increased the glycolytic flux of these cells, suggesting a novel therapeutically targetable cellular mechanism to reduce intra/intermuscular adipose tissue deposition in T2D. Taken together, these findings describe two distinct FAP subsets in human skeletal muscles that participate in modulating the fibro-fatty infiltration of muscles in T2D, a highly prevalent condition in western countries.

 

Figure. Two major FAP populations described by Farup et al., 2020. CD90 positive (CD90+) FAPs and CD90 negative (CD90) FAPs exhibited distinct phenotypic and molecular signatures. These phenotypic differences shed new light on the role of these intriguing cells in modulating muscle degenerative fibro-fatty remodelling in the obese and T2D population.

What we liked of this preprint

The highlight of this preprint is the study of FAP heterogeneity in human muscle and how this diversity might impact skeletal muscle homeostasis. Since most of our understanding of tissue-resident FAPs comes from murine models, this study fills an important gap in our knowledge related to the role of FAPs in human degenerative disorders. Therefore, novel therapies targeting FAPs represent a promising strategy for preventing, testing and treating muscle degeneration in chronic metabolic disorders.

 

Future directions and questions to the authors

  1. The authors described that CD90 discriminates at least two subpopulations of FAPs. How is the expression of CD90 regulated in FAPs following injury and ultimately what is the role of CD90 in controlling FAP fate?
  2. The work is lacking scRNA-seq data sets from obese, T2D and insulin-resistant T2D patients. Perhaps this should help to understand the dynamics and heterogeneity of FAPs in progressive human chronic pathologies and to unveil the molecular and cellular responses of FAPs to weight gain and/or T2D. Are you thinking to perform these experiments?
  3. From what population of endogenous FAPs are CD90+ expressing FAPs descending from. Are you planning to do lineage tracing or fate-mapping experiments (in the mouse) to clarify the hierarchy and clonality of this CD90+ subpopulation of cells and their lineage origin?
  4. It would be interesting to know the factors that participate in the metabolic changes of muscle FAPs associated with T2D and insulin resistance over time.
  5. Since FAPs from healthy muscles support muscle stem cell-dependent regeneration through the secretion of trophic signals, how would be the cross-talk between CD90+ FAP and MuSCs affected in T2D? And finally, what is the behavior of MuSCs in the degenerative microenvironment of T2D patients?
  6. Does insulin downregulate the expression of PDGFRA? Or does the reduction of PDGFRA you observed in insulin-treated T2D patients compared to non-treated T2D patients secondary to the improved metabolic phenotype in the insulin-treated T2D individuals? What muscle-resident cells express the insulin receptor at the single-cell level? Can FAPs become resistant to insulin?

 

Acknowledgements

The authors are grateful to Dr Michael De Lisio (University of Ottawa) for proofreading the highlight and Dr Mate Pálfy for helpful suggestions.

 

References

Skeletal muscle fibrogenic and adipogenic remodelling in obesity and metabolic disorders:

  1. Buras, E. D., Converso-Baran, K., Davis, C. S., Akama, T., Hikage, F., Michele, D. E., … Chun, T.-H. (2019). Fibro-Adipogenic Remodeling of the Diaphragm in Obesity-Associated Respiratory Dysfunction. Diabetes, 68(1), 45–56. https://doi.org/10.2337/db18-0209
  2. Blüher, M. Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol 15, 288–298 (2019). https://doi.org/10.1038/s41574-019-0176-8
  3. Collao N, Farup J, De Lisio M. Role of Metabolic Stress and Exercise in Regulating Fibro/Adipogenic Progenitors. Front Cell Dev Biol. 2020;8:9. Published 2020 Jan 28. doi:10.3389/fcell.2020.00009
  4. Hilton, T. N., Tuttle, L. J., Bohnert, K. L., Mueller, M. J., & Sinacore, D. R. (2008). Excessive Adipose Tissue Infiltration in Skeletal Muscle in Individuals With Obesity, Diabetes Mellitus, and Peripheral Neuropathy: Association With Performance and Function. Physical Therapy, 88(11), 1336–1344. https://doi.org/10.2522/ptj.20080079
  5. Piché ME, Tchernof A, Després JP. Obesity Phenotypes, Diabetes, and Cardiovascular Diseases [published correction appears in Circ Res. 2020 Jul 17;127(3):e107]. Circ Res. 2020;126(11):1477-1500. doi:10.1161/CIRCRESAHA.120.316101
  6. Tam, C. S., Covington, J. D., Bajpeyi, S., Tchoukalova, Y., Burk, D., Johannsen, D. L., … Ravussin, E. (2014). Weight Gain Reveals Dramatic Increases in Skeletal Muscle Extracellular Matrix Remodeling. The Journal of Clinical Endocrinology & Metabolism, 99(5), 1749–1757. https://doi.org/10.1210/jc.2013-4381
  7. Teng S, Huang P. The effect of type 2 diabetes mellitus and obesity on muscle progenitor cell function. Stem Cell Res Ther. 2019;10(1):103. Published 2019 Mar 21. doi:10.1186/s13287-019-1186-0

FAPs and their lineage in muscle health, regeneration and disease:

  1. Contreras O, Rebolledo DL, Oyarzún JE, Olguín HC, Brandan E. Connective tissue cells expressing fibro/adipogenic progenitor markers increase under chronic damage: relevance in fibroblast-myofibroblast differentiation and skeletal muscle fibrosis. Cell Tissue Res. 2016;364(3):647-660. doi:10.1007/s00441-015-2343-0
  2. Eisner, C., Cummings, M., Johnston, G., Tung, L.W., Groppa, E., Chang, C. and Rossi, F.M. (2020), Murine Tissue‐Resident PDGFRα+ Fibro‐Adipogenic Progenitors Spontaneously Acquire Osteogenic Phenotype in an Altered Inflammatory Environment. J Bone Miner Res, 35: 1525-1534. doi:10.1002/jbmr.4020
  3. Hogarth, M.W., Defour, A., Lazarski, C., Gallardo, E., Diaz Manera, J., Partridge, T.A., Nagaraju, K., Jaiswal, J.K. (2019). Fibroadipogenic progenitors are responsible for muscle loss in limb girdle muscular dystrophy 2B. Nat Commun. 3;10(1):2430. doi: 10.1038/s41467-019-10438-z.
  4. Joe AW, Yi L, Natarajan A, et al. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat Cell Biol. 2010;12(2):153-163. doi:10.1038/ncb2015
  5. Kopinke, D., Roberson, E. C. and Reiter, J. F. (2017). Ciliary hedgehog signaling restricts injury-induced adipogenesis. Cell 170, 340-351.e312. doi:10.1016/j.cell.2017.06.035
  6. Mueller AA, van Velthoven CT, Fukumoto KD, Cheung TH, Rando TA. Intronic polyadenylation of PDGFRalpha in resident stem cells attenuates muscle fibrosis. Nature. 2016; 540:276–279
  7. Reggio A, Rosina M, Krahmer N, et al. Metabolic reprogramming of fibro/adipogenic progenitors facilitates muscle regeneration. Life Sci Alliance. 2020;3(3):e202000646. Published 2020 Feb 4. doi:10.26508/lsa.202000660
  8. Uezumi A, Fukada S, Yamamoto N, et al. Identification and characterization of PDGFRα+ mesenchymal progenitors in human skeletal muscle. Cell Death Dis. 2014;5(4):e1186. Published 2014 Apr 17. doi:10.1038/cddis.2014.161
  9. Uezumi A, Fukada S, Yamamoto N, Takeda S, Tsuchida K. Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat Cell Biol. 2010;12(2):143-152. doi:10.1038/ncb2014
  10. Wosczyna MN, Konishi CT, Perez Carbajal EE, et al. Mesenchymal Stromal Cells Are Required for Regeneration and Homeostatic Maintenance of Skeletal Muscle. Cell Rep. 2019;27(7):2029-2035.e5. doi:10.1016/j.celrep.2019.04.074

Skeletal muscle FAP diversity:

  1. Contreras O, Cruz-Soca M, Theret M, et al. Cross-talk between TGF-β and PDGFRα signaling pathways regulates the fate of stromal fibro-adipogenic progenitors. J Cell Sci. 2019;132(19):jcs232157. Published 2019 Oct 9. doi:10.1242/jcs.232157
  2. De Micheli AJ, Laurilliard EJ, Heinke CL, et al. Single-Cell Analysis of the Muscle Stem Cell Hierarchy Identifies Heterotypic Communication Signals Involved in Skeletal Muscle Regeneration. Cell Rep. 2020;30(10):3583-3595.e5. doi:10.1016/j.celrep.2020.02.067
  3. Giordani L, He GJ, Negroni E, et al. High-Dimensional Single-Cell Cartography Reveals Novel Skeletal Muscle-Resident Cell Populations. Mol Cell. 2019;74(3):609-621.e6. doi:10.1016/j.molcel.2019.02.026
  4. Malecova B, Gatto S, Etxaniz U, et al. Dynamics of cellular states of fibro-adipogenic progenitors during myogenesis and muscular dystrophy. Nat Commun. 2018;9(1):3670. Published 2018 Sep 10. doi:10.1038/s41467-018-06068-6
  5. Marinkovic M, Fuoco C, Sacco F, et al. Fibro-adipogenic progenitors of dystrophic mice are insensitive to NOTCH regulation of adipogenesis. Life Sci Alliance. 2019;2(3):e201900437. Published 2019 Jun 25. doi:10.26508/lsa.201900437
  6. Oprescu SN, Yue F, Qiu J, Brito LF, Kuang S. Temporal Dynamics and Heterogeneity of Cell Populations during Skeletal Muscle Regeneration. iScience. 2020;23(4):100993. doi:10.1016/j.isci.2020.100993
  7. Rubenstein AB, Smith GR, Raue U, et al. Single-cell transcriptional profiles in human skeletal muscle. Sci Rep. 2020;10(1):229. Published 2020 Jan 14. doi:10.1038/s41598-019-57110-6
  8. Scott RW, Arostegui M, Schweitzer R, Rossi FMV, Underhill TM. Hic1 Defines Quiescent Mesenchymal Progenitor Subpopulations with Distinct Functions and Fates in Skeletal Muscle Regeneration. Cell Stem Cell. 2019; 25(6):797-813.e9. doi:10.1016/j.stem.2019.11.004

Tags: diet, extracellular matrix, faps, fibro-adipogenic progenitors, fibroblasts, fibrosis, obesity, skeletal muscle, type 2 diabetes

doi: https://doi.org/10.1242/prelights.24354

Read preprint (1 votes)

Author's response

Jean Farup and Niels Jessen shared

  1. The authors described that CD90 discriminates at least two subpopulations of FAPs. How is the expression of CD90 regulated in FAPs following injury and ultimately what is the role of CD90 in controlling FAP fate?

Given the fact that FAPs have been so poorly described in human skeletal muscle, there is, to our knowledge, no published data on this matter. We still don’t know how the FAP population, in general, behaves during a muscle injury in humans. Mouse studies suggest a rapid increase in FAPs following injury in young mice [1, 2], whereas in old mice the FAP proliferation seems to be reduced or delayed [3]. Concerning our data, the role of CD90+ FAPs in mouse FAPs is not well described. Based on single-cell data from Tabula Muris, CD90 is expressed in some mouse FAPs, so the potential for a phenotype similar to human FAPs is there [4]. Moreover, CD90 has been shown to mark specific fibroblast subsets in mice [5, 6].

While FAPs have not been studied during a muscle injury in humans, TCF7L2+ cells have been shown to accumulate following a muscle injury [7]. We show that human FAPs do express TCF7L2, however, our single-cell RNA data also indicate that other cell types, such as endothelial cells, may express this transcription factor. Therefore, we are unsure if the earlier studies using TCF7L2+ are mirroring FAP behaviour during a muscle injury. Based on the phenotype of CD90+ FAPs we would expect these to accumulate more during a muscle injury since they retain a more clonally potent FAP subpopulation. Provided with the marker panel described in our paper, future studies can examine how human FAPs behaves in the context of muscle injury or other muscle-related diseases.

 

  1. The work is lacking scRNA-seq data sets from obese, T2D and insulin-resistant T2D patients. Perhaps this should help to understand the dynamics and heterogeneity of FAPs in progressive human chronic pathologies and to unveil the molecular and cellular responses of FAPs to weight gain and/or T2D. Are you thinking to perform these experiments?

 

We have considered this and agree that it would be highly interesting. In the present work, we chose to focus on the populations that we identified in non-diabetic muscle and went on to show their relevancy in the context of type 2 diabetes. Our flow-data suggested that neither muscle stem cell, endothelial cell or hematopoietic cell content was significantly altered in type 2 diabetic patients, whereas the FAP content was. We cannot rule our a bias in our flow-sorting markers and therefore confirming our data using single-cell RNA seq or similar would indeed be valuable.

 

  1. From what population of endogenous FAPs are CD90+ expressing FAPs descending from. Are you planning to do lineage tracing or fate-mapping experiments (in the mouse) to clarify the hierarchy and clonality of this CD90+ subpopulation of cells and their lineage origin?

 

This is a good question and of course hard to answer in human skeletal muscle. We have thought about using mouse models to track the cells and also track their behaviour during obesity and insulin resistance. However, this would require that we first examined of the CD90+ FAP phenotype was conserved in mouse FAPs. Moreover, since CD90 is not a unique FAP marker (other cells residing in skeletal muscle, as well as other organs, express CD90), it would be technically challenging to develop such a model. Given the “progenitor” like phenotype, we would predict that most FAPs originate from the CD90+ FAPs and then some cells transition into a CD90- FAP, which may be more committed towards differentiation.

 

  1. It would be interesting to know the factors that participate in the metabolic changes of muscle FAPs associated with T2D and insulin resistance over time.

 

Yes, we agree. Provided with the ability to now prospectively isolate human FAPs using FACS this could be assessed in clinical trials. Real-time metabolic analysis using seahorse is difficult to conduct using freshly isolated cells, as the metabolism is much lower compared to cultured cells. In our paper, we assessed the metabolism using 1×105 freshly sorted cells per well to ensure reliable measures of oxygen consumption rate and extracellular acidification rate. Such cell numbers would require relatively large biopsies to ensure enough cells. Perhaps with some optimization, the required number of cells could be lowered.

 

  1. Since FAPs from healthy muscles support muscle stem cell-dependent regeneration through the secretion of trophic signals, how would be the cross-talk between CD90+ FAP and MuSCs affected in T2D? And finally, what is the behaviour of MuSCs in the degenerative microenvironment of T2D patients?

 

This is a highly interesting question and very important to address to understand the role of FAPs in disease and ageing. There are currently no studies, to our knowledge, describing how human FAPs may effect myofiber or MuSC function. It seems clear from animal studies that FAPs play an important role both during homeostasis and degenerative diseases [2, 8, 9]. We expect that human FAPs have at least some of the same traits. Studies using human muscle-derived “fibroblasts”, which is likely also containing substantial numbers of FAPs, have shown that these may impact myoblast proliferation and differentiation, although the results vary somewhat between studies [7, 10]. This area should be further investigated using FACS isolated human FAPs. It is also interesting to consider what happens when FAPs differentiate into fibroblasts/myofibroblasts or adipocytes concerning the release of cytokines or growth factors which normally serve to maintain myofiber size or function? This might provide one explanation as to why the accumulation of fibrosis and adipocytes results in poor muscle function due to the loss of trophic signalling.

In our study, we didn’t assess the functionality of MuSC in non-diabetics versus diabetic patients. However, we do think this is highly interesting and relevant to address. We would expect that MuSC function (e.g. time-to-first division[11]) would decline in type 2 diabetic patients, similar to the impaired wound healing capacity. Future studies should address this to understand how regenerative capacity is altered in type 2 diabetes to translate findings derived from rodent models into human skeletal muscle.

 

  1. Does insulin downregulate the expression of PDGFRA? Or does the reduction of PDGFRA you observed in insulin-treated T2D patients compared to non-treated T2D patients secondary to the improved metabolic phenotype in the insulin-treated T2D individuals? What muscle-resident cells express the insulin receptor at the single-cell level? Can FAPs become resistant to insulin?

 

We don’t know if insulin would cause downregulation of PDGFRA in FAPs, however, PDGF-AA stimulation does seem to lower PDGFRA protein expression. As for insulin, we know that it increases FAP proliferation and insulin is also a key factor for FAP adipogenesis. Our first interpretation of the lowered PDGFRA expression in the severely insulin-resistant type 2 diabetic patients is therefore differentiation of FAPs into myofibroblasts and adipocytes, which would cause them to reduce PDGFRA expression. This would also explain the more extensive interstitial remodelling in these patients. However, at this point, we cannot rule out a direct effect of insulin on PDGFRA expression.

It seems that several populations of mononuclear express the insulin receptor (we haven’t checked the different INSR variants), however, the expression is particularly high in FAPs. Again, given the proximity of FAPs to vessels, it is interesting to speculate if these are particularly prone to high insulin, glucose or free fatty acid levels. We haven’t examined whether FAPs become insulin resistant in type 2 diabetes, but this is worth investigating. In addition to this, we also speculate if FAPs from type 2 diabetic patients may lose the ability to support muscle mass maintenance and potentially also insulin sensitivity. Given the proximity of FAPs to capillaries, they are likely to influenced by changes in the circulation and respond to changes such as high glucose, insulin or free fatty acids.

 

References

1.Lemos, D.R., et al., Nat Med, 2015. 21(7): p. 786-94 DOI: 10.1038/nm.3869.

2.Madaro, L., et al., Nat Cell Biol, 2018. 20(8): p. 917-927 DOI: 10.1038/s41556-018-0151-y.

3.Lukjanenko, L., et al., Cell Stem Cell, 2019 DOI: 10.1016/j.stem.2018.12.014.

4.Tabula Muris, C., et al., Nature, 2018. 562(7727): p. 367-372 DOI: 10.1038/s41586-018-0590-4.

5.Croft, A.P., et al., Nature, 2019 DOI: 10.1038/s41586-019-1263-7.

6.Mahmoudi, S., et al., Nature, 2019. 574(7779): p. 553-558 DOI: 10.1038/s41586-019-1658-5.

7.Mackey, A.L., et al., J Physiol, 2017 DOI: 10.1113/JP273997.

8.Wosczyna, M.N., et al., Cell Rep, 2019. 27(7): p. 2029-2035 e5 DOI: 10.1016/j.celrep.2019.04.074.

9.Hogarth, M.W., et al., Nat Commun, 2019. 10(1): p. 2430 DOI: 10.1038/s41467-019-10438-z.

10.Bechshoft, C.J.L., et al., J Appl Physiol (1985), 2019. 127(2): p. 342-355 DOI: 10.1152/japplphysiol.00215.2019.

11.Brett, J.O., et al., Nature Metabolism, 2020. 2(4): p. 307-317 DOI: 10.1038/s42255-020-0190-0.

 

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Gestational exposure to high heat-humidity conditions impairs mouse embryonic development

Avinchal Manhas, Amritesh Sarkar, Srimonta Gayen

Selected by 08 July 2024

Girish Kale, preLights peer support

Developmental Biology

Modular control of time and space during vertebrate axis segmentation

Ali Seleit, Ian Brettell, Tomas Fitzgerald, et al.

AND

Natural genetic variation quantitatively regulates heart rate and dimension

Jakob Gierten, Bettina Welz, Tomas Fitzgerald, et al.

Selected by 24 June 2024

Girish Kale, Jennifer Ann Black

Developmental Biology

preLists in the biochemistry category:

BSCB-Biochemical Society 2024 Cell Migration meeting

This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.

 



List by Reinier Prosee

Peer Review in Biomedical Sciences

Communication of scientific knowledge has changed dramatically in recent decades and the public perception of scientific discoveries depends on the peer review process of articles published in scientific journals. Preprints are key vehicles for the dissemination of scientific discoveries, but they are still not properly recognized by the scientific community since peer review is very limited. On the other hand, peer review is very heterogeneous and a fundamental aspect to improve it is to train young scientists on how to think critically and how to evaluate scientific knowledge in a professional way. Thus, this course aims to: i) train students on how to perform peer review of scientific manuscripts in a professional manner; ii) develop students' critical thinking; iii) contribute to the appreciation of preprints as important vehicles for the dissemination of scientific knowledge without restrictions; iv) contribute to the development of students' curricula, as their opinions will be published and indexed on the preLights platform. The evaluations will be based on qualitative analyses of the oral presentations of preprints in the field of biomedical sciences deposited in the bioRxiv server, of the critical reports written by the students, as well as of the participation of the students during the preprints discussions.

 



List by Marcus Oliveira et al.

CellBio 2022 – An ASCB/EMBO Meeting

This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.

 



List by Nadja Hümpfer et al.

20th “Genetics Workshops in Hungary”, Szeged (25th, September)

In this annual conference, Hungarian geneticists, biochemists and biotechnologists presented their works. Link: http://group.szbk.u-szeged.hu/minikonf/archive/prg2021.pdf

 



List by Nándor Lipták

Fibroblasts

The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!

 



List by Osvaldo Contreras

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

 



List by Dey Lab

Cellular metabolism

A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.

 



List by Pablo Ranea Robles

MitoList

This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.

 



List by Sandra Franco Iborra

Also in the bioinformatics category:

‘In preprints’ from Development 2022-2023

A list of the preprints featured in Development's 'In preprints' articles between 2022-2023

 



List by Alex Eve, Katherine Brown

9th International Symposium on the Biology of Vertebrate Sex Determination

This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.

 



List by Martin Estermann

Alumni picks – preLights 5th Birthday

This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.

 



List by Sergio Menchero et al.

Fibroblasts

The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!

 



List by Osvaldo Contreras

Single Cell Biology 2020

A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.

 



List by Alex Eve

Antimicrobials: Discovery, clinical use, and development of resistance

Preprints that describe the discovery of new antimicrobials and any improvements made regarding their clinical use. Includes preprints that detail the factors affecting antimicrobial selection and the development of antimicrobial resistance.

 



List by Zhang-He Goh

Also in the cell biology category:

BSCB-Biochemical Society 2024 Cell Migration meeting

This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.

 



List by Reinier Prosee

‘In preprints’ from Development 2022-2023

A list of the preprints featured in Development's 'In preprints' articles between 2022-2023

 



List by Alex Eve, Katherine Brown

preLights peer support – preprints of interest

This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.

 



List by preLights peer support

The Society for Developmental Biology 82nd Annual Meeting

This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.

 



List by Joyce Yu, Katherine Brown

CSHL 87th Symposium: Stem Cells

Preprints mentioned by speakers at the #CSHLsymp23

 



List by Alex Eve

Journal of Cell Science meeting ‘Imaging Cell Dynamics’

This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.

 



List by Helen Zenner

9th International Symposium on the Biology of Vertebrate Sex Determination

This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.

 



List by Martin Estermann

Alumni picks – preLights 5th Birthday

This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.

 



List by Sergio Menchero et al.

CellBio 2022 – An ASCB/EMBO Meeting

This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.

 



List by Nadja Hümpfer et al.

Fibroblasts

The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!

 



List by Osvaldo Contreras

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.

 



List by Alex Eve

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

 



List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.

 



List by Ana Dorrego-Rivas

BioMalPar XVI: Biology and Pathology of the Malaria Parasite

[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria

 



List by Dey Lab, Samantha Seah

1

Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.

 



List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

 



List by Maiko Kitaoka et al.

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.

 



List by Paul Gerald L. Sanchez and Stefano Vianello

ECFG15 – Fungal biology

Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome

 



List by Hiral Shah

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

 



List by Dey Lab

Autophagy

Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.

 



List by Sandra Malmgren Hill

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.

 



List by Rob Hynds

Cellular metabolism

A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.

 



List by Pablo Ranea Robles

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019

 



List by Dey Lab

MitoList

This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.

 



List by Sandra Franco Iborra

Biophysical Society Annual Meeting 2019

Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA

 



List by Joseph Jose Thottacherry

ASCB/EMBO Annual Meeting 2018

This list relates to preprints that were discussed at the recent ASCB conference.

 



List by Dey Lab, Amanda Haage

Also in the genomics category:

BSCB-Biochemical Society 2024 Cell Migration meeting

This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.

 



List by Reinier Prosee

9th International Symposium on the Biology of Vertebrate Sex Determination

This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.

 



List by Martin Estermann

Semmelweis Symposium 2022: 40th anniversary of international medical education at Semmelweis University

This preList contains preprints discussed during the 'Semmelweis Symposium 2022' (7-9 November), organised around the 40th anniversary of international medical education at Semmelweis University covering a wide range of topics.

 



List by Nándor Lipták

20th “Genetics Workshops in Hungary”, Szeged (25th, September)

In this annual conference, Hungarian geneticists, biochemists and biotechnologists presented their works. Link: http://group.szbk.u-szeged.hu/minikonf/archive/prg2021.pdf

 



List by Nándor Lipták

EMBL Conference: From functional genomics to systems biology

Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020

 



List by Jesus Victorino

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

 



List by Maiko Kitaoka et al.

Zebrafish immunology

A compilation of cutting-edge research that uses the zebrafish as a model system to elucidate novel immunological mechanisms in health and disease.

 



List by Shikha Nayar
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