Development of an in vitro tissue engineered intestine for drug testing

Lead Research Organisation: University College London
Department Name: Institute of Child Health

Abstract

The development of an in vitro gut model that mimics mechanical, secretive and absorptive properties of the human gut could potentially replace experimental animal models. Moreover, a tissue engineered intestine (TEI) using a combination of autologous cells and scaffolds would help to accelerate intestine tissue engineering and overcome limitations related to transplantation. The lack of an appropriate combination of intestinal cells and scaffolds has limited the therapeutic advancement of TEI. It has been suggested that natural scaffolds derived from decellularized organs are preferable since they maintain the signals needed for cell proliferation and differentiation in the extracellular matrix (ECM). Professor De Coppi's group has extensive experience on natural scaffolds and has recently created a natural intestinal scaffold that maintains the crypt-villus architecture. Dr Li's group has developed efficient techniques to isolate and expand human derived stem cells from intestinal crypts into organoids. We are now interested in establishing a collaboration to develop innovative technologies for TEI which could be used in biological research in collaboration with Dr Dal Negro at GSK.

Publications

10 25 50

Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/N503861/1 01/03/2016 29/02/2020
1700992 Studentship BB/N503861/1 01/03/2016 29/02/2020 Alfonso Maria Tedeschi
 
Description the vasculature represent the compound that instruct and orchestrate organ regeneration, homeostasis and function. It is a pivotal compound to regenerate when it gets to recapitolate the function of an organ.
The use of endothelial cells alone cannot regenerate a functional and stable vasculature since, pericytes are required to improve vessels organisation and durability.
This study takes advantage of a co-culture approach to develop an organised, stable and perfusable vasculature within an decellularised rat intestine in order to understand the mechanisms by which endothelial cells (HUVECs) and pericytes (human Mesoangioblasts, MABs) crosstalk in the regeneration process.
Co-culture of HUVECs and MABs into the vasculature of the decellularised intestinal scaffold resulted in HUVECs lining the vessels and MABs located in a perivascular position, sustaining the endothelial durability.
Moreover, HUVECs guide the maturation of Mesoangioblasts towards smooth muscle, which repopulates the smooth muscle layer of the vessels and surrounds the undifferentiated pericytes.
Interestingly, the smooth muscle migrates out of the vessel and repopulates the visceral smooth muscle, supporting the hypothesis that pericytes could be the progenitors of their specific tissue mesoderm.
According to our results, endothelial cells mediate the smooth muscle MABs' differentiation through a process that involve DLL4 - NOTCH pathway and not TGFb.
Finally, Mesoangioblasts allow a better and longer-lasting engraftment in-vivo of the regenerated vasculature which anastomose with the host vasculature.
We confirmed this data taking advantages of a TNAP-AP-CreERT2:R26R mouse model: this model allowed us follow the fate of Perycites AP+ cells after injection with Tamoxifen. After induction of the system, we observed cells invading the smooth muscle layer of the intestine over time. This phenomena was corroborated when, injecting GFP+ MABs into the visceral smooth muscle of adult mice, we observed patches of mature smooth muscle coming from the pericyte precursor.
In conclusion, we engineered an organised, perfusable and long lasting vasculature which features both the vascular and perivascular compartments, delivering an ideal platform which will be used to study the crosstalk with other compounds (such epithelium, nervous system, muscle layer) and finally a graft that mimics the intestinal function for drug testing.
Exploitation Route this is an ideal platform that can be taken forward by adding other intestinal compounds (such as epithelium) to study their crosstalk and test their function
Sectors Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology,Other