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1. Microenvironmental determinants of organized iPSC-cardiomyocyte tissues on synthetic fibrous matrices

   https://doi.org/10.1039/D0BM01247E  

   DePalma, Samuel J. ; Davidson, Christopher D. ; Stis, Austin E. ; Helms, Adam S. ; Baker, Brendon M. ( January 2021 , Biomaterials Science)

   null (Ed.)

   Cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) show great potential for engineering myocardium to study cardiac disease and create regenerative therapies. However, iPSC-CMs typically possess a late embryonic stage phenotype, with cells failing to exhibit markers of mature adult tissue. This is due in part to insufficient knowledge and control of microenvironmental cues required to facilitate the organization and maturation of iPSC-CMs. Here, we employed a cell-adhesive, mechanically tunable synthetic fibrous extracellular matrix (ECM) consisting of electrospun dextran vinyl sulfone (DVS) fibers and examined how biochemical, architectural, and mechanical properties of the ECM impact iPSC-CM tissue assembly and subsequent function. Exploring a multidimensional parameter space spanning cell-adhesive ligand, seeding density, fiber alignment, and stiffness, we found that fibronectin-functionalized DVS matrices composed of highly aligned fibers with low stiffness optimally promoted the organization of functional iPSC-CM tissues. Tissues generated on these matrices demonstrated improved calcium handling and increased end-to-end localization of N-cadherin as compared to micropatterned fibronectin lines or fibronectin-coated glass. Furthermore, DVS matrices supported long-term culture (45 days) of iPSC-CMs; N-cadherin end-to-end localization and connexin43 expression both increased as a function of time in culture. In sum, these findings demonstrate the importance of recapitulating the fibrous myocardial ECM in engineering structurally organized and functional iPSC-CM tissues. 

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2. Aligned Networks of Engineered Fibrillar Fibronectin Guide Cellular Orientation and Motility

   https://doi.org/10.1002/sstr.202000137  

   Neale, Dylan B. ; Muñiz, Ayşe J. ; Jones, Michael S. ; Kim, Do Hoon ; Buschhaus, Johanna M. ; Humphries, Brock A. ; Wang, William Y. ; Baker, Brendon M. ; Raymond, Jeffery E. ; Solorio, Luis ; et al ( March 2021 , Small Structures)

   The extracellular matrix (ECM) influences biological processes associated with tissue development and disease progression. However, robust cell‐free techniques to control fiber alignment of naturally derived ECM proteins, such as fibronectin (Fn), remain elusive. It is demonstrated that controlled hydrodynamics of Fn solutions at the air/fluid interface of porous tessellated polymer scaffolds (TPSs) generates suspended 3D fibrillar networks with alignment across multiple length scales (<1, 1–20 μm, extended to >1 mm). The direction of the fluid flow and the architecture of the polymeric supports influence protein solution flow profiles and, subsequently, the alignment of insoluble Fn fibrils. Aligned networks of fibrillar Fn characteristically alter fibroblast phenotype, indicated by increased directional orientation, enhanced nuclear and cytoskeletal polarity, and highly anisotropic and persistent cell motility when compared with nonaligned 3D networks and 2D substrates. Engineered extracellular matrices (EECMs) establish a critically needed tool for both fundamental and applied cell biology studies, with potential applications in diverse areas such as cancer biology and regenerative medicine.

    

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3. Extracellular Matrix-Based Biomaterials for Cardiovascular Tissue Engineering

   https://doi.org/10.3390/jcdd8110137  

   Khanna, Astha ; Zamani, Maedeh ; Huang, Ngan F. ( November 2021 , Journal of Cardiovascular Development and Disease)

   Regenerative medicine and tissue engineering strategies have made remarkable progress in remodeling, replacing, and regenerating damaged cardiovascular tissues. The design of three-dimensional (3D) scaffolds with appropriate biochemical and mechanical characteristics is critical for engineering tissue-engineered replacements. The extracellular matrix (ECM) is a dynamic scaffolding structure characterized by tissue-specific biochemical, biophysical, and mechanical properties that modulates cellular behavior and activates highly regulated signaling pathways. In light of technological advancements, biomaterial-based scaffolds have been developed that better mimic physiological ECM properties, provide signaling cues that modulate cellular behavior, and form functional tissues and organs. In this review, we summarize the in vitro, pre-clinical, and clinical research models that have been employed in the design of ECM-based biomaterials for cardiovascular regenerative medicine. We highlight the research advancements in the incorporation of ECM components into biomaterial-based scaffolds, the engineering of increasingly complex structures using biofabrication and spatial patterning techniques, the regulation of ECMs on vascular differentiation and function, and the translation of ECM-based scaffolds for vascular graft applications. Finally, we discuss the challenges, future perspectives, and directions in the design of next-generation ECM-based biomaterials for cardiovascular tissue engineering and clinical translation. 

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4. The pericyte microenvironment during vascular development

   https://doi.org/10.1111/micc.12554  

   Payne, Laura B. ; Zhao, Huaning ; James, Carissa C. ; Darden, Jordan ; McGuire, David ; Taylor, Sarah ; Smyth, James W. ; Chappell, John C. ( May 2019 , Microcirculation)

   Vascular pericytes provide critical contributions to the formation and integrity of the blood vessel wall within the microcirculation. Pericytes maintain vascular stability and homeostasis by promoting endothelial cell junctions and depositing extracellular matrix (ECM) components within the vascular basement membrane, among other vital functions. As their importance in sustaining microvessel health within various tissues and organs continues to emerge, so does their role in a number of pathological conditions including cancer, diabetic retinopathy, and neurological disorders. Here, we review vascular pericyte contributions to the development and remodeling of the microcirculation, with a focus on the local microenvironment during these processes. We discuss observations of their earliest involvement in vascular development and essential cues for their recruitment to the remodeling endothelium. Pericyte involvement in the angiogenic sprouting context is also considered with specific attention to crosstalk with endothelial cells such as through signaling regulation and ECM deposition. We also address specific aspects of the collective cell migration and dynamic interactions between pericytes and endothelial cells during angiogenic sprouting. Lastly, we discuss pericyte contributions to mechanisms underlying the transition from active vessel remodeling to the maturation and quiescence phase of vascular development.

    

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5. Microengineering 3D Collagen Matrices with Tumor‐Mimetic Gradients in Fiber Alignment

   https://doi.org/10.1002/adfm.202308071  

   Joshi, Indranil M. ; Mansouri, Mehran ; Ahmed, Adeel ; De Silva, Dinindu ; Simon, Richard A. ; Esmaili, Poorya ; Desa, Danielle E. ; Elias, Tresa M. ; Brown, III, Edward B. ; Abhyankar, Vinay V. ( December 2023 , Advanced Functional Materials)

   Collagen fibers in the 3D tumor microenvironment (TME) exhibit complex alignment landscapes that are critical in directing cell migration through a process called contact guidance. Previous in vitro work studying this phenomenon has focused on quantifying cell responses in uniformly aligned environments. However, the TME also features short‐range gradients in fiber alignment that result from cell‐induced traction forces. Although the influence of graded biophysical taxis cues is well established, cell responses to physiological alignment gradients remain largely unexplored. In this work, fiber alignment gradients in biopsy samples are characterized and recreated using a new microfluidic biofabrication technique to achieve tunable sub‐millimeter to millimeter scale gradients. This study represents the first successful engineering of continuous alignment gradients in soft, natural biomaterials. Migration experiments on graded alignment show that human umbilical vein endothelial cells (HUVECs) exhibit increased directionality, persistence, and speed compared to uniform and unaligned fiber architectures. Similarly, patterned MDA‐MB‐231 breast cancer cell aggregates exhibit biased migration toward increasing fiber alignment, suggesting a role for alignment gradients as a taxis cue. This user‐friendly approach, requiring no specialized equipment, is anticipated to offer new insights into the biophysical cues that cells interpret as they traverse the extracellular matrix (ECM), with broad applicability in healthy and diseased tissue environments.

    

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