Use of perfusion decellularized liver for islet cell recellularization
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Publication Number
US-10213525-B2
Publication Date
2019-02-26
Expiration Date
Abstract
The invention provides a method for preparing a perfusion based islet cell containing extracellular matrix of liver, an islet cell recellularized extracellular matrix, and methods of using the recellularized matrix.
Core Innovation
The invention relates to preparing a graft using a perfusion decellularized extracellular matrix of a mammalian liver, a portion of a liver, a liver lobe or a portion thereof that is >8 cm3. The graft is prepared by providing two populations of mammalian cells and contacting them with the perfusion decellularized extracellular matrix under conditions and for a period of time. The perfusion decellularized extracellular matrix provides a vasculature that can be re-endothelialized and a matrix that can be re-cellularized.
A first population of mammalian cells comprising endothelial cells, stem cells capable of differentiation into endothelial cells, progenitor cells capable of differentiation into endothelial cells, or any combination thereof is used to re-endothelialize a vasculature of the perfusion decellularized extracellular matrix. A second population of mammalian cells comprising insulin producing cells, stem cells capable of differentiation into insulin producing cells, progenitor cells capable of differentiation into insulin producing cells, or any combination thereof is used to recellularize the perfusion decellularized extracellular matrix to generate insulin producing tissue within the graft. If the first population is stem cells or progenitor cells, the conditions allow differentiation into endothelial cells, and if the second population is stem cells or progenitor cells, the conditions allow differentiation into insulin producing cells.
The described approach uses perfusion decellularization to preserve intact vascular/microvascular structure and other organ features such as vascular conduits and capsule integrity. The graft design supports subsequent cell seeding and graft function by enabling re-endothelialization and recellularization of the perfusion decellularized extracellular matrix with endothelial and insulin producing cell types. The disclosed examples also include options for xenogeneic and allogeneic cells and matrix, and delivery by injection and/or perfusion, including serially or sequentially.
Claims Coverage
The independent claim covers a graft-preparation method that uses a perfusion decellularized mammalian liver extracellular matrix and two cell populations to re-endothelialize the vasculature and recellularize the matrix to produce insulin producing tissue. The claim contains two coordinated inventive feature sets: (i) re-endothelialization with endothelial or endothelial-competent cells, and (ii) recellularization with insulin producing cells or insulin-competent cells, with differentiation supported when stem or progenitor cells are used.
Perfusion decellularized mammalian liver extracellular matrix graft scaffold
Providing a perfusion decellularized extracellular matrix of a mammalian liver, a portion of a liver, a liver lobe or a portion thereof that is >8 cm3.
Two-cell population contact for re-endothelialization and recellularization
Providing two populations of cells comprising a first population of mammalian cells comprising endothelial cells, stem cells capable of differentiation into endothelial cells, progenitor cells capable of differentiation into endothelial cells, or any combination thereof and a second population of mammalian cells comprising insulin producing cells, stem cells capable of differentiation into insulin producing cells, progenitor cells capable of differentiation into insulin producing cells, or any combination thereof; and contacting the perfusion decellularized extracellular matrix and the two populations of cells under conditions and for a period of time so that cells in the first population re-endothelialize a vasculature of the perfusion decellularized extracellular matrix and cells in the second population recellularize the perfusion decellularized extracellular matrix.
Conditioned differentiation for endothelial and insulin producing lineages
Wherein if the cells in the first population are stem cells or progenitor cells, the conditions allow for those cells to differentiate into endothelial cells, and wherein if the cells in the second population are stem cells or progenitor cells, the conditions allow for those cells to differentiate into insulin producing cells.
Across the independent claim, the central coverage is the contacting of a perfusion decellularized mammalian liver extracellular matrix scaffold with two distinct mammalian cell populations under conditions that drive re-endothelialization of the scaffold vasculature and recellularization to produce insulin producing tissue, with differentiation supported when stem or progenitor cells are used.
Stated Advantages
Enables re-endothelialization of the vasculature of the perfusion decellularized extracellular matrix and recellularization of the perfusion decellularized extracellular matrix.
Supports differentiation of stem cells or progenitor cells into endothelial cells and insulin producing cells under the stated conditions.
Documented Applications
Preparing a graft intended to improve blood-glucose control in mammals with reduced insulin control using re-endothelialized and insulin producing cell grafts.
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