Tissue-Engineered Endothelial and Epithelial Implants Differentially and Synergistically Regulate Tissue Repair

Abstract

Endothelial implants restore vascular homeostasis after injury without reconstituting vascular architecture. Endothelial cells line the vascular epithelium and underlying vasa vasorum precluding distinction between cellular controls. Unlike blood vessels, the airway epithelium is highly differentiated and distinct from endothelial cells that line the bronchial vasa allowing investigation of the differential control tissue engineered cells may provide in airways and blood vessels. Through airway injury and cell culture models, tissue engineered implants of the bronchial epithelium and endothelium were found to promote synergistic repair of the airway through biochemical regulation of the airway microenvironment. While epithelial cells modulate local tissue composition and reaction, endothelial cells preserve the epithelium; together their relative impact was enhanced suggesting both cell types act synergistically for airway repair.

Description

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0001]Work described herein was supported by Federal Grant No. R01, GM49039, awarded by the National Institutes of Health. The Government has certain rights to this invention.BACKGROUND[0002]Airways, intestines, ureters, fallopian tubes and other tubular structures possess a trilaminate form which offers structural integrity and flow modulation, as well as profound regulation of local inflammation, thrombosis and hemostasis, proliferation and remodeling. In these structures, a loose fibrous adventitia is replete with coursing arterioles, venules and neural forms, a middle muscularis layer provides control of luminal dimensions and tone, and a surface layer contains cells that biochemically regulate the wall response, and sense flow and luminal contents.[0003]In airway disorders—such as asthma and chronic obstructive pulmonary disease (COPD)—functional imbalance is tightly associated with remodeling of airway structure. R...

AI Technical Summary

Benefits of technology

[0005]The present invention exploits the discovery that a therapeutic composition comprising cells and a biocompatible matrix, when provided locally to a tubular structure, such as an airway, can reduce or inhibit abnormal or pathological tissue remodeling typified by luminal narrowing, epithelial damage, mesenchymal cell hyperplasia, collagen deposition, hypervascularity, and inflammatory cell infiltration.

[0009]In other embodiments, the therapeutic composition reduces an area of the injury, one or more of hypervascularity, angiogenesis, neovascularization, fibrosis, collagen deposition, inflammatory cell infiltration or necrosis, the extent of luminal narrowing or obstruction of the airway, or mesenchymal hyperplasia or hypervascularity at or nearby the site of injury. In another embodiment, the therapeutic composition enhances repair of injured epithelial cells or tissue. In another embodiment, the cells secrete an effective amount of prostaglandin E2. In another embodiment, the cells reduce proliferation of lung fibroblasts. In another embodiment, the cells are autogenic, allogenic, or xenogenic.

[0013]In another embodiment, the injury is an injury to a tubular structure, an airway, a tracheal injury or a bronchial injury. In another embodiment, the injury is as a result of disease, trauma or medical procedure. In other embodiments, the composition reduces the area of the injury, reduces one or more of hypervascularity, angiogenesis, neovascularization, fibrosis or necrosis, or reduces extent of luminal obstruction of the airway. In another embodiment, the composition enhances epithelial repair. In another embodiment, the composition reduces mesenchymal hyperplasia at or nearby the site of injury. In another embodiment, the composition reduces hypervascularity at or nearby the site of injury. In another embodiment, the cells secrete an effective amount of prostaglandin E2. In another embodiment, the cells reduce proliferation of lung fibroblasts. In another embodiment, the cells are autogenic, allogenic, or xenogenic.

[0015]In another embodiment, the injury is an airway injury and the therapeutic composition reduces stridor resulting from the airway injury. In a further embodiment, the injury results from disease, trauma or medical procedure. In another embodiment, the therapeutic composition reduces angiogenesis and / or neovascularization resulting from the injury.

Problems solved by technology

In airway disorders—such as asthma and chronic obstructive pulmonary disease (COPD)—functional imbalance is tightly associated with remodeling of airway structure.

Current treatments for airway disorders and disorders of other tubular structures are limited and often have adverse consequences.

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