New concepts for generating interspecies chimeras using human pluripotent stem cells

Angeles, Alejandro De Los; Wu, Jun

doi:10.1007/s13238-021-00880-5

Cited by 13 publications

(8 citation statements)

References 18 publications

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“…These early experiments made a clear distinction between interspecies and intraspecies chimerism. In other words, the evolutionary distance between two species may be inversely correlated with the extent of chimerism (de Los Angeles and Wu, 2022). This section reviews various interspecies chimera formation rates and chimerism during development.…”

Section: Interspecies Barriers In Chimerasmentioning

confidence: 99%

“…Recently, this concept has been extended to large-animal interspecies, yet other barriers such as donor cell pluripotency, cell-cell competition, and other potential xenogeneic incompatibility barriers result in low chimeric efficacies ( Wu et al, 2017 ; Garry and Garry, 2019 ; de Los Angeles and Wu, 2022 ; Roodgar et al, 2022 ). Chimerism during and beyond the post-implantation stage of development presents a separate set of challenges ( Figure 1 ).…”

Section: Blastocyst Complementationmentioning

confidence: 99%

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Towards human organ generation using interspecies blastocyst complementation: Challenges and perspectives for therapy

Sarmah

Sawada

Hwang

et al. 2023

Front. Cell Dev. Biol.

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Millions of people suffer from end-stage refractory diseases. The ideal treatment option for terminally ill patients is organ transplantation. However, donor organs are in absolute shortage, and sadly, most patients die while waiting for a donor organ. To date, no technology has achieved long-term sustainable patient-derived organ generation. In this regard, emerging technologies of chimeric human organ production via blastocyst complementation (BC) holds great promise. To take human organ generation via BC and transplantation to the next step, we reviewed current emerging organ generation technologies and the associated efficiency of chimera formation in human cells from the standpoint of developmental biology.

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Section: Interspecies Barriers In Chimerasmentioning

confidence: 99%

Section: Blastocyst Complementationmentioning

confidence: 99%

Towards human organ generation using interspecies blastocyst complementation: Challenges and perspectives for therapy

Sarmah

Sawada

Hwang

et al. 2023

Front. Cell Dev. Biol.

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“…Time-lapse confocal microscopy revealed better survival of H9 hES cells during co-culture with Mavs KO mEpiSCs than with WT mEpiSCs (Supplementary Video 1). Next, we calculated the cell densities (cell number per cm 2 ) of live H9 hES cells and mEpiSCs in co-culture and separate culture daily until they grew to confluency (days [1][2][3][4][5]. A more rapid elimination of H9 hES cells was observed during co-culture with WT than with Mavs KO mEpiSCs (Fig.…”

Section: Main Textmentioning

confidence: 99%

“…The technique of generating interspecies chimeras using human pluripotent stem cells (hPSCs) is a promising in vivo platform to study human development and offers a potential source for growing human donor organs in animals 1, 2 . Although robust chimerism can be achieved between closely related species 3, 4 , it is far more difficult to generate chimeras between evolutionarily distant species 5 .…”

Section: Main Textmentioning

confidence: 99%

RNA Sensing and Innate Immunity Constitutes a Barrier for Interspecies Chimerism

Sun

Sakurai

et al. 2023

Preprint

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Interspecies chimera formation with human pluripotent stem cells (PSCs) holds great promise to generate humanized animal models and provide donor organs for transplant. However, the approach is currently limited by low levels of human cells ultimately represented in chimeric embryos. Different strategies have been developed to improve chimerism by genetically editing donor human PSCs. To date, however, it remains unexplored if human chimerism can be enhanced in animals through modifying the host embryos. Leveraging the interspecies PSC competition model, here we discovered retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling, an RNA sensor, in winner cells plays an important role in the competitive interactions between co-cultured mouse and human PSCs. We found that genetic inactivation of Ddx58/Ifih1-Mavs-Irf7 axis compromised the winner status of mouse PSCs and their ability to outcompete PSCs from evolutionarily distant species during co-culture. Furthermore, by using Mavs-deficient mouse embryos we substantially improved unmodified donor human cell survival. Comparative transcriptome analyses based on species-specific sequences suggest contact-dependent human-to-mouse transfer of RNAs likely plays a part in mediating the cross-species interactions. Taken together, these findings establish a previously unrecognized role of RNA sensing and innate immunity in winner cells during cell competition and provides a proof-of-concept for modifying host embryos, rather than donor PSCs, to enhance interspecies chimerism.

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“…Primed PSCs cannot form chimeric embryos efficiently(Huang et al , 2018). Recent works showed that PSCs in the formative state have the higher potential to contribute to chimeric embryonic development than the primed state PSCs (De Los Angeles & Wu, 2021; Yu et al , 2021b). Thus, a full understanding of pluripotent states regulation is critical for obtaining formative and naïve pluripotency states to pave the way for translational applications of human PSCs, including human embryonic stem cells (hESCs) (Yu et al ., 2021b).…”

Section: Introductionmentioning

confidence: 99%

Musashi1 and its short C-terminal variants regulate pluripotency states in embryonic stem cells

Chen

Zhang

Han

et al. 2022

Preprint

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Musashi1 (MSI1) is a marker for adult stem cells, but little is known for its expression and function in pluripotent stem cells (PSCs). Here we report that MSI1 is expressed in embryonic stem cells (ESCs) and is required for pluripotency maintenance. We found that there exit short c-terminal MSI1 variants (MSI1-C, hMSI1272-362 or mMSI1138-362) in naïve but not primed ESCs. When overexpressed, MSI1 and MSI1-C variants facilitate primed-to-naïve pluripotency transition by elevating the pluripotency of primed hESCs toward a formative-like state, enable better survival of hESCs in human-mouse interspecies cell completion, and enhance the ability of blastoid formation of hESCs after naïve induction. Mechanistically, we show that the MSI1-C variants, though lacking RNA recognition motifs, bind to RNAs, enhance stress resistance and upregulate DNA damage repair genes. Thus, this study demonstrates that ESCs utilize MSI1 and the newly identified short MSI1-C proteins as double swords to regulate pluripotency states.

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New concepts for generating interspecies chimeras using human pluripotent stem cells

Cited by 13 publications

References 18 publications

Towards human organ generation using interspecies blastocyst complementation: Challenges and perspectives for therapy

Towards human organ generation using interspecies blastocyst complementation: Challenges and perspectives for therapy

RNA Sensing and Innate Immunity Constitutes a Barrier for Interspecies Chimerism

Musashi1 and its short C-terminal variants regulate pluripotency states in embryonic stem cells

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