Article

Self-organized vascular networks from human pluripotent stem cells in a synthetic matrix

Department of Chemical and Biomolecular Engineering, Johns Hopkins Physical Sciences-Oncology Center and Institute for NanoBioTechnology, and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 07/2013; 110(31). DOI: 10.1073/pnas.1306562110
Source: PubMed

ABSTRACT The success of tissue regenerative therapies is contingent on functional and multicellular vasculature within the redeveloping tissue. Although endothelial cells (ECs), which compose the vasculature's inner lining, are intrinsically able to form nascent networks, these structures regress without the recruitment of pericytes, supporting cells that surround microvessel endothelium. Reconstruction of typical in vivo microvascular architecture traditionally has been done using distinct cell sources of ECs and pericytes within naturally occurring matrices; however, the limited sources of clinically relevant human cells and the inherent chemical and physical properties of natural materials hamper the translational potential of these approaches. Here we derived a bicellular vascular population from human pluripotent stem cells (hPSCs) that undergoes morphogenesis and assembly in a synthetic matrix. We found that hPSCs can be induced to codifferentiate into early vascular cells (EVCs) in a clinically relevant strategy amenable to multiple hPSC lines. These EVCs can mature into ECs and pericytes, and can self-organize to form microvascular networks in an engineered matrix. These engineered human vascular networks survive implantation, integrate with the host vasculature, and establish blood flow. This integrated approach, in which a derived bicellular population is exploited for its intrinsic self-assembly capability to create microvasculature in a deliverable matrix, has vast ramifications for vascular construction and regenerative medicine.

1 Follower
 · 
64 Views
  • Source
    • "The phase image of the vascular network and a close-up image of the vascular vessel cross-section were shown here. Adapted with permission from Ref. [105]. Copyright 2013, United States National Academy of Sciences. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human pluripotent stem cells (hPSCs) provide promising resources for regenerating tissues and organs and modeling development and diseases in vitro. To fulfill their promise, the fate, function, and organization of hPSCs need to be precisely regulated in a three-dimensional (3D) environment to mimic cellular structures and functions of native tissues and organs. In the past decade, innovations in 3D culture systems with functional biomaterials have enabled efficient and versatile control of hPSC fate at the cellular level. However, we are just at the beginning of bringing hPSC-based regeneration and development and disease modeling to the tissue and organ levels. In this review, we summarize existing bioengineered culture platforms for controlling hPSC fate and function by regulating inductive mechanical and biochemical cues coexisting in the synthetic cell microenvironment. We highlight recent excitements in developing 3D hPSC-based in vitro tissue and organ models with in vivo-like cellular structures, interactions, and functions. We further discuss an emerging multifaceted mechanotransductive signaling network - with transcriptional coactivators YAP and TAZ at the center stage - that regulate fates and behaviors of mammalian cells, including hPSCs. Future development of 3D biomaterial systems should incorporate dynamically modulated mechanical and chemical properties targeting specific intracellular signaling events leading to desirable hPSC fate patterning and functional tissue formation in 3D. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Biomaterials 06/2015; 52. DOI:10.1016/j.biomaterials.2015.01.078 · 8.31 Impact Factor
  • Source
    • "hPSC-derived endothelial progenitors and endothelial cells may provide building blocks for the establishment of in vitro disease models for screening and development of drugs to treat these diseases. Functionality of hPSC-derived endothelial cells has been shown using in vitro cell culture platforms and in vivo animal models (Adams et al., 2013; Kusuma et al., 2013; Orlova et al., 2014; Samuel et al., 2013; Wang et al., 2007). Similar to other somatic cells derived from hPSCs, differentiated CD31 + endothelial cells exhibited functional heterogeneity (Rufaihah et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human pluripotent stem cell (hPSC)-derived endothelial cells and their progenitors may provide the means for vascularization of tissue-engineered constructs and can serve as models to study vascular development and disease. Here, we report a method to efficiently produce endothelial cells from hPSCs via GSK3 inhibition and culture in defined media to direct hPSC differentiation to CD34(+)CD31(+) endothelial progenitors. Exogenous vascular endothelial growth factor (VEGF) treatment was dispensable, and endothelial progenitor differentiation was ?-catenin dependent. Furthermore, by clonal analysis, we showed that CD34(+)CD31(+)CD117(+)TIE-2(+) endothelial progenitors were multipotent, capable of differentiating into calponin-expressing smooth muscle cells and CD31(+)CD144(+)vWF(+)I-CAM1(+) endothelial cells. These endothelial cells were capable of 20 population doublings, formed tube-like structures, imported acetylated low-density lipoprotein, and maintained a dynamic barrier function. This study provides a rapid and efficient method for production of hPSC-derived endothelial progenitors and endothelial cells and identifies WNT/?-catenin signaling as a primary regulator for generating vascular cells from hPSCs.
    Stem Cell Reports 11/2014; 3(5):804-16. DOI:10.1016/j.stemcr.2014.09.005 · 5.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Human pluripotent stem cells (hPSCs) hold great promise for revolutionizing regenerative medicine for their potential applications in disease modeling, drug discovery, and cellular therapy. Many their applications require robust and scalable expansion of hPSCs, even under settings compliant to good clinical practices. Rapid evolution of media and substrates provided safer and more defined culture conditions for long-term expansion of undifferentiated hPSCs in either adhesion or suspension. With well-designed automatic systems or fully controlled bioreactors, production of a clinically relevant quantity of hPSCs could be achieved in the near future. The goal is to find a scalable, xeno-free, chemically defined, and economic culture system for clinical-grade expansion of hPSCs that complies the requirements of current good manufacturing practices. This review provides an updated overview of the current development and challenges on the way to accomplish this goal, including discussions on basic principles for bioprocess design, serum-free media, extracellular matric or synthesized substrate, microcarrier- or cell aggregate-based suspension culture, and scalability and practicality of equipment.
    Annals of Biomedical Engineering 10/2013; 42(7). DOI:10.1007/s10439-013-0921-4 · 3.23 Impact Factor
Show more