{"id":{"repo_id":"toronto-retro","oai_identifier":"oai:utoronto.scholaris.ca:1807/101435"},"canonical_url":"https://search.dev.ndltd.org/etd/toronto-retro/oai:utoronto.scholaris.ca:1807/101435","repository":{"repo_id":"toronto-retro","name":"University of Toronto","base_url":"https://utoronto.scholaris.ca/server/oai/request"},"display":{"title":"Generation of induced progenitor-like (iPL) cells using interrupted reprogramming","abstract":"Regenerative medicine is constrained by suboptimal cell sources with either limited or uncontrolled proliferation and/or incompletely restricted differentiation. We developed a novel \"interrupted reprogramming\" strategy without traversing the pluripotent state, to generate \"induced Progenitor-Like (iPL) cells\" using carefully timed transient expression of induced Pluripotent Stem (iPS) cell reprogramming factors (Oct4, Sox2, Klf4 and c-Myc; OSKM). Interrupted reprogramming is not only able to achieve controlled expansion of the selected cell type, but results in the \"de-differentiation\" of the cells to a progenitor-like state while preserving the parental lineage commitment to generate a limited range of functional progeny. Lineage-specific iPL cells can be derived from distinct airway epithelial populations and function as region-specific progenitor cells. For example, bronchiolar progenitor-like iPL cells can be derived from mature Club cells (Club-iPL cells) and give rise to Club cells, goblet cells and functional CFTR-expressing ciliated epithelium. Embryonic bipotent progenitor-like iPL cells can be derived from adult alveolar type II cells (AEC-II-iPL cells) and the iPL process results in the rescue of the in vitro limited clonogenic capacity of AEC-II cells. These highly specified iPL populations are functional and therapeutic that are capable of directly contributing to lung regeneration through engraftment and differentiation. In vivo, Club-iPL cells were able to repopulate CFTR-deficient bronchiolar epithelium and AEC-II-iPL cells showed utility in ameliorating bleomycin-induced pulmonary fibrosis. This interrupted reprogramming process could be metronomically applied both in vitro and in vivo, to achieve controlled progenitor-like proliferation. Furthermore, harnessing the residual epigenetic “memory” and the plasticity existing in the early stage of the reprogramming process, interrupted reprogramming is able to rejuvenate aged endogenous progenitor AEC-II cells to a youthful state by ameliorating multiple hallmarks of aging, including impaired self-renewal, declined telomerase activity, mitochondrial DNA damages and the epigenome histone alteration. Importantly, cellular identity and function of parental AEC-II cells were maintained, thereby generating large numbers of younger AEC-II cells. In summary, this novel interrupted reprogramming strategy will allow the production of highly specified functional therapeutic populations which can potentially have significant implications for regenerative medicine, specifically for, cell replacement therapy, biohybrid devices, disease modelling, and drug screening for human diseases.","abstract_html":"Regenerative medicine is constrained by suboptimal cell sources with either limited or uncontrolled proliferation and/or incompletely restricted differentiation. We developed a novel "interrupted reprogramming" strategy without traversing the pluripotent state, to generate "induced Progenitor-Like (iPL) cells" using carefully timed transient expression of induced Pluripotent Stem (iPS) cell reprogramming factors (Oct4, Sox2, Klf4 and c-Myc; OSKM). Interrupted reprogramming is not only able to achieve controlled expansion of the selected cell type, but results in the "de-differentiation" of the cells to a progenitor-like state while preserving the parental lineage commitment to generate a limited range of functional progeny. Lineage-specific iPL cells can be derived from distinct airway epithelial populations and function as region-specific progenitor cells. For example, bronchiolar progenitor-like iPL cells can be derived from mature Club cells (Club-iPL cells) and give rise to Club cells, goblet cells and functional CFTR-expressing ciliated epithelium. Embryonic bipotent progenitor-like iPL cells can be derived from adult alveolar type II cells (AEC-II-iPL cells) and the iPL process results in the rescue of the in vitro limited clonogenic capacity of AEC-II cells. These highly specified iPL populations are functional and therapeutic that are capable of directly contributing to lung regeneration through engraftment and differentiation. In vivo, Club-iPL cells were able to repopulate CFTR-deficient bronchiolar epithelium and AEC-II-iPL cells showed utility in ameliorating bleomycin-induced pulmonary fibrosis. This interrupted reprogramming process could be metronomically applied both in vitro and in vivo, to achieve controlled progenitor-like proliferation. Furthermore, harnessing the residual epigenetic “memory” and the plasticity existing in the early stage of the reprogramming process, interrupted reprogramming is able to rejuvenate aged endogenous progenitor AEC-II cells to a youthful state by ameliorating multiple hallmarks of aging, including impaired self-renewal, declined telomerase activity, mitochondrial DNA damages and the epigenome histone alteration. Importantly, cellular identity and function of parental AEC-II cells were maintained, thereby generating large numbers of younger AEC-II cells. In summary, this novel interrupted reprogramming strategy will allow the production of highly specified functional therapeutic populations which can potentially have significant implications for regenerative medicine, specifically for, cell replacement therapy, biohybrid devices, disease modelling, and drug screening for human diseases.","abstract_has_math":false,"creators":["GUO, LI"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":"Medical Science","school":null,"contributors":[],"advisors":["Waddell, Thomas"],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018-06","date_published":"2018-06","updated_at":"2026-07-27T21:28:11Z","subjects":[],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/1807/101435","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Waddell, Thomas"]},{"key":"dc:contributor.department","label":"Department","values":["Medical Science"]},{"key":"dc:creator","label":"Author","values":["GUO, LI"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2018-06"]},{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2020-06-30T04:00:15Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2020-06-30T04:00:15Z"]},{"key":"dc:date.issued","label":"Date","values":["2018-06"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/1807/101435"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Regenerative medicine is constrained by suboptimal cell sources with either limited or uncontrolled proliferation and/or incompletely restricted differentiation. We developed a novel \"interrupted reprogramming\" strategy without traversing the pluripotent state, to generate \"induced Progenitor-Like (iPL) cells\" using carefully timed transient expression of induced Pluripotent Stem (iPS) cell reprogramming factors (Oct4, Sox2, Klf4 and c-Myc; OSKM). Interrupted reprogramming is not only able to achieve controlled expansion of the selected cell type, but results in the \"de-differentiation\" of the cells to a progenitor-like state while preserving the parental lineage commitment to generate a limited range of functional progeny. Lineage-specific iPL cells can be derived from distinct airway epithelial populations and function as region-specific progenitor cells. For example, bronchiolar progenitor-like iPL cells can be derived from mature Club cells (Club-iPL cells) and give rise to Club cells, goblet cells and functional CFTR-expressing ciliated epithelium. Embryonic bipotent progenitor-like iPL cells can be derived from adult alveolar type II cells (AEC-II-iPL cells) and the iPL process results in the rescue of the in vitro limited clonogenic capacity of AEC-II cells. These highly specified iPL populations are functional and therapeutic that are capable of directly contributing to lung regeneration through engraftment and differentiation. In vivo, Club-iPL cells were able to repopulate CFTR-deficient bronchiolar epithelium and AEC-II-iPL cells showed utility in ameliorating bleomycin-induced pulmonary fibrosis. This interrupted reprogramming process could be metronomically applied both in vitro and in vivo, to achieve controlled progenitor-like proliferation. Furthermore, harnessing the residual epigenetic “memory” and the plasticity existing in the early stage of the reprogramming process, interrupted reprogramming is able to rejuvenate aged endogenous progenitor AEC-II cells to a youthful state by ameliorating multiple hallmarks of aging, including impaired self-renewal, declined telomerase activity, mitochondrial DNA damages and the epigenome histone alteration. Importantly, cellular identity and function of parental AEC-II cells were maintained, thereby generating large numbers of younger AEC-II cells. In summary, this novel interrupted reprogramming strategy will allow the production of highly specified functional therapeutic populations which can potentially have significant implications for regenerative medicine, specifically for, cell replacement therapy, biohybrid devices, disease modelling, and drug screening for human diseases."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Ph.D."]},{"key":"dc:title","label":"Title","values":["Generation of induced progenitor-like (iPL) cells using interrupted reprogramming"]}]}],"canonical_facts":{"dc:contributor.advisor":["Waddell, Thomas"],"dc:contributor.department":["Medical Science"],"dc:creator":["GUO, LI"],"dc:date":["2018-06"],"dc:date.accessioned":["2020-06-30T04:00:15Z"],"dc:date.available":["2020-06-30T04:00:15Z"],"dc:date.issued":["2018-06"],"dc:description.abstract":["Regenerative medicine is constrained by suboptimal cell sources with either limited or uncontrolled proliferation and/or incompletely restricted differentiation. We developed a novel \"interrupted reprogramming\" strategy without traversing the pluripotent state, to generate \"induced Progenitor-Like (iPL) cells\" using carefully timed transient expression of induced Pluripotent Stem (iPS) cell reprogramming factors (Oct4, Sox2, Klf4 and c-Myc; OSKM). Interrupted reprogramming is not only able to achieve controlled expansion of the selected cell type, but results in the \"de-differentiation\" of the cells to a progenitor-like state while preserving the parental lineage commitment to generate a limited range of functional progeny. Lineage-specific iPL cells can be derived from distinct airway epithelial populations and function as region-specific progenitor cells. For example, bronchiolar progenitor-like iPL cells can be derived from mature Club cells (Club-iPL cells) and give rise to Club cells, goblet cells and functional CFTR-expressing ciliated epithelium. Embryonic bipotent progenitor-like iPL cells can be derived from adult alveolar type II cells (AEC-II-iPL cells) and the iPL process results in the rescue of the in vitro limited clonogenic capacity of AEC-II cells. These highly specified iPL populations are functional and therapeutic that are capable of directly contributing to lung regeneration through engraftment and differentiation. In vivo, Club-iPL cells were able to repopulate CFTR-deficient bronchiolar epithelium and AEC-II-iPL cells showed utility in ameliorating bleomycin-induced pulmonary fibrosis. This interrupted reprogramming process could be metronomically applied both in vitro and in vivo, to achieve controlled progenitor-like proliferation. Furthermore, harnessing the residual epigenetic “memory” and the plasticity existing in the early stage of the reprogramming process, interrupted reprogramming is able to rejuvenate aged endogenous progenitor AEC-II cells to a youthful state by ameliorating multiple hallmarks of aging, including impaired self-renewal, declined telomerase activity, mitochondrial DNA damages and the epigenome histone alteration. Importantly, cellular identity and function of parental AEC-II cells were maintained, thereby generating large numbers of younger AEC-II cells. In summary, this novel interrupted reprogramming strategy will allow the production of highly specified functional therapeutic populations which can potentially have significant implications for regenerative medicine, specifically for, cell replacement therapy, biohybrid devices, disease modelling, and drug screening for human diseases."],"dc:description.degree":["Ph.D."],"dc:identifier.uri":["http://hdl.handle.net/1807/101435"],"dc:title":["Generation of induced progenitor-like (iPL) cells using interrupted reprogramming"],"dc:type":["Thesis"]},"updated_at":"2026-07-27T21:28:11Z"}