Use of a hyaluronan and methylcellulose hydrogel to deliver neural stem cells to the stroke-injured brain
-
1
University of Toronto, Chemical Engineering and Applied Chemistry, Canada
-
2
University of Toronto, Institute of Biomaterials and Biomedical Engineering, Canada
-
3
Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Canada
-
4
University of Toronto, Institute of Medical Science, Canada
-
5
University of Toronto, Department of Chemistry, Canada
Introduction: Worldwide 15 million people will suffer from a stroke each year, and up to two-thirds of survivors will experience life-long functional deficits. Despite the high prevalence of stroke, no clinical treatment exists that can replace lost cells and restore function. Recent regenerative medicine strategies have focused on the delivery of an exogenous source of cells to both directly replace lost neurons and glia as well as provide trophic support to endogenous cells. While cell transplantation is a promising strategy to regenerate stroke-injured tissues, current delivery techniques suffer from low cell survival. To increase cell survival following transplantation, our lab has developed a hydrogel composed of a physical blend of hyaluronan and methylcellulose, HAMC, and demonstrated its ability to improve cell delivery and increase survival in a model of spinal cord injury[1] and retinal regeneration[2]. We hypothesize that the use of HAMC to deliver mouse or human neural precursor cells will result in improved cell survival and functional recovery in a rat model of stroke. The goals of this work are to determine if the use of HAMC can 1) maintain cell viability prior to delivery, and 2) increase cell survival and functional recovery when transplanted in vivo.
Materials and Methods: HAMC hydrogels were produced using a physical blend of 0.5%/0.5% w/v sterile methylcellulose and hyaluronan reconstituted in artificial cerebralspinal fluid (aCSF). First, the ability of HAMC to improve cell survival even before transplantation was tested by encapsulating mouse precursor cells (stem and progenitors) (mNPCs) and human neuroepithelial stem cells (hNECs)[3] in 3D HAMC and left on ice for 6 or 24 hours. Next, mNPCs were delivered to a mouse stroke model to determine if HAMC promotes the survival of cells after transplantation. Lastly, we wanted to translate the work with mNPCs towards a clinically-relevant model, and so tested the use of HAMC to deliver induced pluripotent stem cell-derived hNECs into the stroke-injured rat brain. hNECs were differentiated into neural precursor cells (hNPCs) and transplanted into the stroke-injured rat brain.
Results and Discussion: HAMC significantly increased mNPC and hNECs survival when cells were encapsulated in HAMC and stored on ice after 6 hours compared to aCSF. This suggests that storing cells in HAMC prior to transplantation will reduce cell death and increase the number of live cells being delivered to the brain. In mice, HAMC increased cell survival of undifferentiated mNPCs and ultimately resulted in functional recovery after endothelin-1 stroke-injury[4]. In rats, HAMC also improved survival of hNPCs in an endothelin-1 stroke-injury. In ongoing studies, we are investigating behavioural recovery in rats.
Conclusions: This study demonstrates the importance of the delivery vehicle on the success of cell transplantation and tissue regeneration in the stroke-injured brain using both mouse and rat models and mouse and human neural stem cells, respectively. This contributes to the broader field of regenerative medicine.
We are grateful to CIHR and NSERC for funding
References:
[1] Mothe AJ, Tam RY, Zahir T, Tator CH, Shoichet MS. 2013. Biomaterials 34: 3775-83.
[2] Ballios BG, Cooke MJ, van der Kooy D, Shoichet MS. 2010. Biomaterials 31: 2555-2564.
[3] Varga BV, Faiz M, Linderoth E, Nagy A. 2015. Under revision in Cell Stem Cell
[4] Ballios BG, Cooke MJ, Donaldson L, Coles BLK, Morshead CM, van der Kooy D, Shoichet MS. 2015. Stem Cell Reports 4:1-15.
Keywords:
Hydrogel,
Regenerative Medicine,
stem cell,
biomedical application
Conference:
10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016.
Presentation Type:
Poster
Topic:
Biomaterials for therapeutic delivery
Citation:
Payne
SL,
Cooke
MJ,
Anandakumaran
P,
Varga
B,
Morshead
C,
Nagy
A and
Shoichet
MS
(2016). Use of a hyaluronan and methylcellulose hydrogel to deliver neural stem cells to the stroke-injured brain.
Front. Bioeng. Biotechnol.
Conference Abstract:
10th World Biomaterials Congress.
doi: 10.3389/conf.FBIOE.2016.01.01163
Copyright:
The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers.
They are made available through the Frontiers publishing platform as a service to conference organizers and presenters.
The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated.
Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed.
For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions.
Received:
27 Mar 2016;
Published Online:
30 Mar 2016.
*
Correspondence:
Dr. Samantha L Payne, University of Toronto, Chemical Engineering and Applied Chemistry, Toronto, ON, Canada, Email1
Dr. Michael J Cooke, University of Toronto, Institute of Biomaterials and Biomedical Engineering, Toronto, ON, Canada, Email2
Dr. Cindi Morshead, University of Toronto, Institute of Medical Science, Toronto, ON, Canada, Email3
Dr. Andras Nagy, Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada, Email4
Dr. Molly S Shoichet, University of Toronto, Chemical Engineering and Applied Chemistry, Toronto, ON, Canada, Email5