Resolving Cell Fate Decisions during Somatic Cell Reprogramming by Single-Cell RNA-Seq

Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs), which is a highly heterogeneous process. Here we report the cell fate continuum during somatic cell reprogramming at single-cell resolution. We first develop SOT to analyze cell fate continuum from Oct4/Sox2/Klf4- or OSK-...

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Published in	Molecular cell Vol. 73; no. 4; pp. 815 - 829.e7
Main Authors	Guo, Lin, Lin, Lihui, Wang, Xiaoshan, Gao, Mingwei, Cao, Shangtao, Mai, Yuanbang, Wu, Fang, Kuang, Junqi, Liu, He, Yang, Jiaqi, Chu, Shilong, Song, Hong, Li, Dongwei, Liu, Yujian, Wu, Kaixin, Liu, Jiadong, Wang, Jinyong, Pan, Guangjin, Hutchins, Andrew P., Liu, Jing, Pei, Duanqing, Chen, Jiekai
Format	Journal Article
Language	English
Published	United States Elsevier Inc 21.02.2019
Subjects	bifurcation cell fate decision Dppa5a induced pluripotent stem cells Interferon gamma keratinocytes Klf4 Oct4 reprogramming sequence analysis single-cell RNA sequencing somatic cells Sox2 reprogramming single-cell RNA sequencing Dppa5a Oct4 Sox2 bifurcation cell fate decision induced pluripotent stem cells Klf4 Interferon gamma
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Abstract	Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs), which is a highly heterogeneous process. Here we report the cell fate continuum during somatic cell reprogramming at single-cell resolution. We first develop SOT to analyze cell fate continuum from Oct4/Sox2/Klf4- or OSK-mediated reprogramming and show that cells bifurcate into two categories, reprogramming potential (RP) or non-reprogramming (NR). We further show that Klf4 contributes to Cd34+/Fxyd5+/Psca+ keratinocyte-like NR fate and that IFN-γ impedes the final transition to chimera-competent pluripotency along the RP cells. We analyze more than 150,000 single cells from both OSK and chemical reprograming and identify additional NR/RP bifurcation points. Our work reveals a generic bifurcation model for cell fate decisions during somatic cell reprogramming that may be applicable to other systems and inspire further improvements for reprogramming. [Display omitted] •Cell fate continuum generated by somatic reprogramming•Single-cell Orientation Tracing (SOT) for fate trajectory detection•Two non-reprogramming trajectories regulated by Klf4 and IFN-γ•A generic bifurcation model for cell fate decisions Guo et al. report the cell fate continuum during induced pluripotent stem cell (iPSC) reprogramming at single-cell resolution. By developing SOT as a new analytic tool, they identify several previously unknown bifurcation points along the reprogramming path and propose a generic bifurcation model for cell fate decisions.
AbstractList	Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs), which is a highly heterogeneous process. Here we report the cell fate continuum during somatic cell reprogramming at single-cell resolution. We first develop SOT to analyze cell fate continuum from Oct4/Sox2/Klf4- or OSK-mediated reprogramming and show that cells bifurcate into two categories, reprogramming potential (RP) or non-reprogramming (NR). We further show that Klf4 contributes to Cd34+/Fxyd5+/Psca+ keratinocyte-like NR fate and that IFN-γ impedes the final transition to chimera-competent pluripotency along the RP cells. We analyze more than 150,000 single cells from both OSK and chemical reprograming and identify additional NR/RP bifurcation points. Our work reveals a generic bifurcation model for cell fate decisions during somatic cell reprogramming that may be applicable to other systems and inspire further improvements for reprogramming. [Display omitted] •Cell fate continuum generated by somatic reprogramming•Single-cell Orientation Tracing (SOT) for fate trajectory detection•Two non-reprogramming trajectories regulated by Klf4 and IFN-γ•A generic bifurcation model for cell fate decisions Guo et al. report the cell fate continuum during induced pluripotent stem cell (iPSC) reprogramming at single-cell resolution. By developing SOT as a new analytic tool, they identify several previously unknown bifurcation points along the reprogramming path and propose a generic bifurcation model for cell fate decisions. Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs), which is a highly heterogeneous process. Here we report the cell fate continuum during somatic cell reprogramming at single-cell resolution. We first develop SOT to analyze cell fate continuum from Oct4/Sox2/Klf4- or OSK-mediated reprogramming and show that cells bifurcate into two categories, reprogramming potential (RP) or non-reprogramming (NR). We further show that Klf4 contributes to Cd34+/Fxyd5+/Psca+ keratinocyte-like NR fate and that IFN-γ impedes the final transition to chimera-competent pluripotency along the RP cells. We analyze more than 150,000 single cells from both OSK and chemical reprograming and identify additional NR/RP bifurcation points. Our work reveals a generic bifurcation model for cell fate decisions during somatic cell reprogramming that may be applicable to other systems and inspire further improvements for reprogramming. Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs), which is a highly heterogeneous process. Here we report the cell fate continuum during somatic cell reprogramming at single-cell resolution. We first develop SOT to analyze cell fate continuum from Oct4/Sox2/Klf4- or OSK-mediated reprogramming and show that cells bifurcate into two categories, reprogramming potential (RP) or non-reprogramming (NR). We further show that Klf4 contributes to Cd34+/Fxyd5+/Psca+ keratinocyte-like NR fate and that IFN-γ impedes the final transition to chimera-competent pluripotency along the RP cells. We analyze more than 150,000 single cells from both OSK and chemical reprograming and identify additional NR/RP bifurcation points. Our work reveals a generic bifurcation model for cell fate decisions during somatic cell reprogramming that may be applicable to other systems and inspire further improvements for reprogramming.Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs), which is a highly heterogeneous process. Here we report the cell fate continuum during somatic cell reprogramming at single-cell resolution. We first develop SOT to analyze cell fate continuum from Oct4/Sox2/Klf4- or OSK-mediated reprogramming and show that cells bifurcate into two categories, reprogramming potential (RP) or non-reprogramming (NR). We further show that Klf4 contributes to Cd34+/Fxyd5+/Psca+ keratinocyte-like NR fate and that IFN-γ impedes the final transition to chimera-competent pluripotency along the RP cells. We analyze more than 150,000 single cells from both OSK and chemical reprograming and identify additional NR/RP bifurcation points. Our work reveals a generic bifurcation model for cell fate decisions during somatic cell reprogramming that may be applicable to other systems and inspire further improvements for reprogramming.
Author	Wang, Xiaoshan Liu, He Pei, Duanqing Liu, Jing Gao, Mingwei Wu, Kaixin Kuang, Junqi Yang, Jiaqi Guo, Lin Chen, Jiekai Song, Hong Pan, Guangjin Hutchins, Andrew P. Wang, Jinyong Lin, Lihui Liu, Jiadong Chu, Shilong Li, Dongwei Liu, Yujian Cao, Shangtao Mai, Yuanbang Wu, Fang
Author_xml	– sequence: 1 givenname: Lin surname: Guo fullname: Guo, Lin organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 2 givenname: Lihui surname: Lin fullname: Lin, Lihui organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 3 givenname: Xiaoshan surname: Wang fullname: Wang, Xiaoshan organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 4 givenname: Mingwei surname: Gao fullname: Gao, Mingwei organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 5 givenname: Shangtao surname: Cao fullname: Cao, Shangtao organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 6 givenname: Yuanbang surname: Mai fullname: Mai, Yuanbang organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 7 givenname: Fang surname: Wu fullname: Wu, Fang organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 8 givenname: Junqi surname: Kuang fullname: Kuang, Junqi organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 9 givenname: He surname: Liu fullname: Liu, He organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 10 givenname: Jiaqi surname: Yang fullname: Yang, Jiaqi organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 11 givenname: Shilong surname: Chu fullname: Chu, Shilong organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 12 givenname: Hong surname: Song fullname: Song, Hong organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 13 givenname: Dongwei surname: Li fullname: Li, Dongwei organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 14 givenname: Yujian surname: Liu fullname: Liu, Yujian organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 15 givenname: Kaixin surname: Wu fullname: Wu, Kaixin organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 16 givenname: Jiadong surname: Liu fullname: Liu, Jiadong organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 17 givenname: Jinyong surname: Wang fullname: Wang, Jinyong organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 18 givenname: Guangjin surname: Pan fullname: Pan, Guangjin organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 19 givenname: Andrew P. surname: Hutchins fullname: Hutchins, Andrew P. organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 20 givenname: Jing surname: Liu fullname: Liu, Jing organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 21 givenname: Duanqing surname: Pei fullname: Pei, Duanqing email: pei_duanqing@gibh.ac.cn organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China – sequence: 22 givenname: Jiekai orcidid: 0000-0001-5168-7074 surname: Chen fullname: Chen, Jiekai email: chen_jiekai@gibh.ac.cn organization: CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/30772174$$D View this record in MEDLINE/PubMed
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Snippet	Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs), which is a highly heterogeneous process. Here we report the cell fate continuum...
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SubjectTerms	bifurcation cell fate decision Dppa5a induced pluripotent stem cells Interferon gamma keratinocytes Klf4 Oct4 reprogramming sequence analysis single-cell RNA sequencing somatic cells Sox2
Title	Resolving Cell Fate Decisions during Somatic Cell Reprogramming by Single-Cell RNA-Seq
URI	https://dx.doi.org/10.1016/j.molcel.2019.01.042 https://www.ncbi.nlm.nih.gov/pubmed/30772174 https://www.proquest.com/docview/2183188396 https://www.proquest.com/docview/2221022638
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