STEM CELL AND HYPOXIA-BASED APPROACHES TO ENGINEERING BLOOD VESSELS

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dc.contributor.advisorCheng, Linzhaoen_US
dc.contributor.authorKusuma, Sravantien_US
dc.contributor.committeeMemberGerecht, Sharonen_US
dc.contributor.committeeMemberMac Gabhann, Feilimen_US
dc.date.accessioned2015-02-11T04:03:16Z
dc.date.available2015-02-11T04:03:16Z
dc.date.created2014-12en_US
dc.date.issued2014-05-19en_US
dc.date.submittedDecember 2014en_US
dc.description.abstractThe success of tissue regenerative therapies is contingent upon functional and multicellular vasculature within the redeveloping tissue. Endothelial cells (ECs), which comprise the vasculature’s inner lining, are intrinsically able to form nascent networks; however, without recruitment of pericytes, supporting cells that surround microvessel endothelium, these endothelial-only structures regress. To reconstruct a typical in vivo microvascular architecture, distinct cell sources of ECs and pericytes have traditionally been used within naturally occurring extracellular matrices (ECMs). However, the limited clinically-relevant human cell sources and inherent chemical and physical properties of natural materials hamper the translational potential of these approaches. Human pluripotent stem cells (hPSCs) are an unlimited source of progenitors from which vascular cells may be derived. Controlled and robust differentiation of hPSCs toward vascular lineages is critical for the advancement and future of patient-specific vascular therapeutics. In this work, we first derived a bicellular vascular population of ECs and pericytes, termed early vascular cells (EVCs), from hPSCs that undergoes vascular morphogenesis in a synthetic matrix to form networks that integrate with host vasculature. Next, we found that low oxygen environments enhance endothelial lineage commitment in EVCs. Subsequently, we compared arterial and venous ECs to an adult stem cell population, endothelial colony forming cells (ECFCs), revealing that ECFCs deposited abundant ECM; mature ECs only produced these ECM proteins under hypoxic conditions via hypoxia-inducible factors 1α and 2α. Finally, we found that EVCs differentiated under low oxygen conditions could produce copious amounts of collagen IV and fibronectin as well as angiogenic growth factors. EVCs differentiated under atmospheric conditions did not demonstrate such abundant ECM expression. Collectively, these findings reveal that control over microenvironmental cues via appropriate signaling molecules is able to robustly produce critical cells of the vasculature, which may in turn serve as novel therapies for vascular diseases or be incorporated into engineered tissue.en_US
dc.format.mimetypeapplication/pdfen_US
dc.identifier.urihttp://jhir.library.jhu.edu/handle/1774.2/37132
dc.languageen
dc.publisherJohns Hopkins University
dc.subjectEndothelial cellsen_US
dc.subjectStem cellsen_US
dc.titleSTEM CELL AND HYPOXIA-BASED APPROACHES TO ENGINEERING BLOOD VESSELSen_US
dc.typeThesisen_US
dc.type.materialtexten_US
thesis.degree.departmentBiomedical Engineeringen_US
thesis.degree.disciplineBiomedical Engineeringen_US
thesis.degree.grantorJohns Hopkins Universityen_US
thesis.degree.grantorSchool of Medicineen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePh.D.en_US
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