Bone Marrow Grafts for Spinal Cord Repair
Human Bone Marrow Stromal Grafts in Combination with Decorin for Repair
for the Injured Spinal Cord
Chief Investigators: Associate Professor Paul Simmons, Dr Giles Plant, Dr Stuart
Hodgetts, Professor Silviu Itescu,
Lead Organisation: StepAhead Australia
TAC Neurotrauma Funding: $736,614
Project Dates: 14 August 2007 – 13 August 2010
Background:
Spinal cord injury (SCI) results in devastating disconnection of descending motor and
ascending sensory pathways, resulting in paralysis below the lesion. Even partial
restoration of damaged spinal tracts could result in major improvements in
upper/lower limb function, increasing the injured person’s independence and reducing
the reliance on carers. Our novel repair strategy for SCI incorporates highly purified,
multipotent human bone marrow stromal cells (hBMSCs) to stimulate axonal
regrowth, improve tissue sparing, and prevent ongoing tissue degeneration. In
addition to stimulating axonal growth, other treatments are needed to diminish the
inhibitory environment of the lesion site.
Aims:
The overall aim was to isolate and transplant hBMSCs from spinal cord injured
patients and use them to repair the injured mammalian spinal cord (SC) after acute
(immediate) and chronic (long term) SCI, in combination with the naturally occurring
proven scar reducing compound Decorin.
Methods:
Phase 1: Donor hBMSCs were isolated from patients and their growth promoting
potential either with or without decorin was assessed in vitro using neurite growth of
ganglion explant cultures in combination with Decorin (Core and non-core isoforms)
and/or hBMSC co-cultures. Immunostaining was used to reveal whether the donor
hBMSCs expressed neuronal marker profiles, whilst microscopic examination
revealed hBMSC’s capacity to myelinate in vitro (myelination is an essential repair
mechanism for the correct functioning of neurons).
Phases 2 and 3: Nude (immunodeficient) rats were subjected to moderate acute (short
term, Phase 2) and chronic (longer term, Phase 3) spinal cord injury (SCI) and treated
with a combination of Decorin infusion (both isoforms) and/or hBMSC
transplantation. SCI was performed using the NYU Impactor device. Acute and
chronic SCI animals were treated with Decorin infusion and/or hBMSC
transplantation at 1wk or 2mo after injury respectively. Functional (locomotory)
recovery was assessed using an open field assay (BBB) for up to 3mo post SCI. For
each regime animals were sampled at various stages following treatment and analysed
for; (i) immunohistochemical staining to reveal neuronal marker expression profiles
within and around the injury site, (ii) injury cyst size and morphological analysis of
the injury site to determine the amount of tissue sparing, (iii) macrophage infiltration
and (iv) glial scarring in and around the injury site.
Results:
Donor hBMSC transplantation markedly improves functional and morphological
recovery after acute and chronic SCI. Functional recovery is not significantly
improved in animals subjected to Decorin infusion via pump (either isoform)
compared to control (injury only) animals in both acute and chronic SCI. Decorin
treatment does appear to prolong the survival of transplanted donor cells, as well as
reduce the amount of infiltrating immune cells responsible for clearing damaged
tissue and debris. Finally, Decorin modestly improves the amount of tissue spared
following both acute and chronic SCI.
Conclusions:
Whilst Decorin treatment did not improve functional recovery after SCI, and did not
enhance the marked improvements in recovery after hBMSC transplantation, it may
serve best in combinatorial repair strategies by prolonging donor cell survival,
reducing the inflammatory response and enhancing tissue sparing after SCI.
Publications:
HODGETTS SI, PLANT GW, HARVEY AR. Chapter 14. Spinal Cord Injury: Experimental Animal
Models and Relation to Human Therapy. In Watson, C., Paxinos G, Kayalioglu G, Heise C, editors.
The Spinal Cord. Academic Press; 2008 p.209-237.
Presentations:
PLANT G. Human bone marrow stromal cell transplants (hBMSCs) for the treatment of acute and
chronic spinal cord injuries. Third Australian Biothereapeutics and Regenerative Medicine Forum;
2007 December 1, Margaret River, Australia.
PLANT GW. Olfactory ensheathing glia: mechanisms of myelination. Molecular Neuroscience &
Neurotrophins in Health and Disease, The Howard Florey Institute; 2008 November 6, Melbourne,
Australia.
PLANT GW. Improved functional recovery after transplantation of human bone marrow stromal cells
(hBMSCs) from spinal cord injured patients into the chronic injured rat spinal cord. Asia Pacific
Symposium on Nanobionics; 2008 June 22-25, Wollongong, Australia.
HODGETTS SI, SIMMONS P, HAYLOCK D, PLANT GW. Improved Functional Recovery After
Transplantation of Human Bone Marrow Stromal Cells (hBMSCs) from Spinal Cord Injured Patients
into the Acute and Chroni Injured Rat Spinal Cord. Annual Scientific Meeting of the Haematology
Society of Australia and New Zealand, The Australian and New Zealand Society of Blood Transfusion
and the Australian Society of Thrombosis and Haemostasis (HAA); 2008 October 19-22, Perth,
Australia.
HODGETTS S, SIMMONS P, HAYLOCK D, PLANT G. Improved functional recovery after
transplantation of human bone marrow stromal stem cells (hBMSCs) into the acute and chronic injured
rat spinal cord. 28th Meeting of the Australian Neuroscience Society Incorporated; 2008 January 22,
Tasmania, Australia.
PLANT G. Improved functional recovery after human bone marrow stromal stem cells (hBMSCs)
transplantation into the acute and chronic injured spinal cord. 1st Trilateral Australia, Japan and China
symposium on Biotherapeutics and Tissue; 2008 May 28-29, Japan.
PLANT GW, LOVETT S, LEE SV, BUCKLEY A, SIMMONS P, HAYLOCK D, HODGETTS S.
Human bone marrow stromal stem cells (hBMSCs)from spinal cord injures (SCI) patients transplanted
into rat spinal cords after complete transection. 13th International Symposium on Neural Regeneration;
2009 December 9-13, Asilomar, USA.
HODGETTS S, LEE SV, BUCKLEY A, SIMMONS P, HAYLOCK D, PLANT GW. Improved
Functional Recovery Using Human Bone Marrow Stromal Stem Cells (hBMSCs) From Spinal Cord
Injured Patients Transplanted Into the Acute and Chronic Injured Rat Spinal Cord. 13th International
Symposium on Neural Regeneration; 2009 December 9-13, Asilomar, USA.
HODGETTS SI. Assessing regeneration in rodent models of spinal cord injury. Spinal Cord Injury
Workshop, 6th Congress of the International Society for Autonomic Neuroscience; 2009 September 5,
Sydney, Australia.
HODGETTS, S. The State of Play of non-Surgical Treatments for Spinal Cord Repair. Royal
Australasian College of Surgeons 10th Annual Scientific Congress; 2010 May 4-7, Perth, Australia.