Pluripotent stem cell-derived myogenic progenitors remodel their molecular signature upon in vivo engraftment

Incitti, Tania; Magli, Alessandro; Darabi, Radbod; Yuan, Ce; Lin, Karena; Arpke, Robert W.; Azzag, Karim; Yamamoto, Ami; Stewart, Ron; Thomson, James A.; Kyba, Michael; Perlingeiro, Rita C.R.

doi:10.1073/pnas.1808303116

Cited by 41 publications

(61 citation statements)

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“…Such differences in the composition of the MuSC niche might explain the specificity and plasticity of transcriptomes we observed. Our finding is in agreement with a previous report [ 86 ], indicating that pluripotent stem cell-derived myogenic progenitors remodel partially their molecular signature towards an adult quiescent MuSC transcriptome upon in vivo engraftment. Importantly, our data show that TA MuSCs re-isolated after engrafting and regeneration display important transcriptome differences with their pre-grafting TA MuSCs counterparts.…”

Section: Discussionsupporting

confidence: 94%

Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation

et al. 2020

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Adult skeletal muscles are maintained during homeostasis and regenerated upon injury by muscle stem cells (MuSCs). A heterogeneity in self-renewal, differentiation and regeneration properties has been reported for MuSCs based on their anatomical location. Although MuSCs derived from extraocular muscles (EOM) have a higher regenerative capacity than those derived from limb muscles, the molecular determinants that govern these differences remain undefined. Here we show that EOM and limb MuSCs have distinct DNA methylation signatures associated with enhancers of location-specific genes, and that the EOM transcriptome is reprogrammed following transplantation into a limb muscle environment. Notably, EOM MuSCs expressed host-site specific positional Hox codes after engraftment and self-renewal within the host muscle. However, about 10% of EOM-specific genes showed engraftment-resistant expression, pointing to cell-intrinsic molecular determinants of the higher engraftment potential of EOM MuSCs. Our results underscore the molecular diversity of distinct MuSC populations and molecularly define their plasticity in response to microenvironmental cues. These findings provide insights into strategies designed to improve the functional capacity of MuSCs in the context of regenerative medicine.

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Section: Discussionsupporting

confidence: 94%

Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation

et al. 2020

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“…Our analysis of EOM and TA MuSCs re-isolated after engrafting each population into injured TA muscle followed by regeneration revealed a global reprogramming of EOM transcriptome towards a TA MuSC transcriptome, indicating that the extracellular environment strongly determines the location-specific signatures we identified. This observation is in agreement with a previous report84 , indicating that stem cell-derived myogenic progenitors remodel partially their molecular signature towards an adult quiescent MuSC transcriptome upon in vivo engraftment. Importantly, our data show that TA MuSCs re-isolated after engrafting and regeneration display important transcriptome differences with their pre-grafting TA MuSCs counterparts.…”

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confidence: 94%

Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation

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Hernando-Herraez

et al. 2020

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20Adult skeletal muscles are maintained during homeostasis and regenerated upon injury by muscle stem 21 cells (MuSCs). A heterogeneity in self-renewal, differentiation and regeneration properties has been 22 reported for MuSCs based on their anatomical location. Although MuSCs derived from extraocular 23 muscles (EOM) have a higher regenerative capacity than those derived from limb muscles, the 24 molecular determinants that govern these differences remain undefined. Here we show that EOM and 25 limb MuSCs have distinct DNA methylation signatures associated with enhancers of location-specific 26 genes, and that the EOM transcriptome is reprogrammed following transplantation into a limb muscle 27 environment. Notably, EOM MuSCs expressed host-site specific positional Hox codes after engraftment 28 and self-renewal within the host muscle. However, about 10% of EOM-specific genes showed 29 engraftment-resistant expression, pointing to cell-intrinsic molecular determinants of the higher 30 engraftment potential of EOM MuSCs. Our results underscore the molecular diversity of distinct MuSC 31 populations and molecularly define their plasticity in response to microenvironmental cues. These 32 findings provide insights into strategies designed to improve the functional capacity of MuSCs in the 33 context of regenerative medicine. 34 35 41 proven to be challenging for muscular dystrophies, as they require delivering enough functional MuSCs 42 to the right muscle groups and ex vivo amplification of healthy MuSCs results in a major decline in their 43 regenerative capacity and stemness properties 16 . 44 45 Most of the knowledge about MuSC biology arises from the study of limb muscles, whereas MuSCs 46 from other muscle groups remain less well characterized. Extraocular muscles (EOMs) are responsible 47 75 76 Here we performed parallel DNA methylation and transcriptome sequencing to characterize the specific 77 identity of adult mouse EOM and limb MuSCs at the molecular level. We used heterotopic 78 transplantation of EOM MuSCs into limb muscles to challenge their fate and assess their plasticity. We 79 4show that their specific identity is mostly niche-driven as they adopt a limb-like molecular signature. 80 Nevertheless, we also identify EOM-specific genes that resist reprogramming by the microenvironment, 81 indicating potential candidates to manipulate in limb-derived MuSCs for improving their regenerative 82 capacity in the context of cellular therapies. 83 84 RESULTS 85 To investigate the molecular differences between EOM and TA MuSCs in vivo, MuSCs from both 86 locations were isolated by FACS (Fluorescence-Activated Cell Sorting) from 10 adult Tg:Pax7-nGFP 17 87 mice and processed for RNA-sequencing and BS-sequencing as in 47,48 (Figure 1A). Unsupervised 88 Principal Component Analysis (PCA) on the transcriptomes revealed clear discrimination between TA 89 and EOM MuSCs samples, indicating location-specific transcriptional identities (Figure 1B). To further 90 investigate these transcriptional signatures...

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“…This level of engraftment is in agreement with our previous xenograft studies ( Darabi et al., 2012 ). Of note, much higher numbers of donor-derived satellite cells were detected in our mouse-to-mouse transplantation studies in the presence or absence of pre-conditioning ( Azzag et al., 2020 ; Incitti et al., 2019 ).…”

Section: Resultsmentioning

confidence: 69%

Pluripotent stem cell-derived myogenic progenitors remodel their molecular signature upon in vivo engraftment

Cited by 41 publications

References 39 publications

Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation

Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation

Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation

Genomic Safe Harbor Expression of PAX7 for the Generation of Engraftable Myogenic Progenitors

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