Project 1

"Human bone marrow stromal cells (hBMSC) in combination with Decorin for repair of the injured spinal cord."

Project Description

Hypothesis:

This research project aims to show that transplantation of hBMSCs, in combination with the scar reducing compound Decorin will provide a favourable environment within the injured Spinal Cord (SC) by reducing the extent of injury (tissue sparing) and promoting regeneration (and other endogenous repair mechanisms not yet known) following spinal cord injury (SCI).

Objectives:

The overall objective over the three years of the project is to isolate and transplant human bone marrow stromal cells (hBMSCs) from spinal cord injured patients and use them  to repair the injured mammalian spinal cord (SC) after acute (immediate) and chronic (long term) spinal cord injury (SCI), in combination with the naturally occurring proven scar reducing compound Decorin.

The primary aim of this research is to show in the rat model improved functional recovery after SCI can be achieved with the combination of hBMSCs and Decorin. Longer term, the knowledge gained from this project will impact neurotrauma by guiding new clinical strategies in the treatment of acute and chronic SCI. 

Outcomes

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 & 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 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.

Recommendations

The amount of time that decorin isoforms should be delivered, and the method of delivery to the lesion site could be investigated further to determine the optimal time and delivery method into the contused spinal cord.

The extent to which decorin may provide any functional recovery after contusion SCI remains unclear, but may be related to delivery.

It is also unclear as to why treatment with either isoform of decorin appears to provide the same outcome in any treatment regime.

Decorin may at least be incorporated into combinatorial treatments in both acute and chronic contusion injuries in order to provide a possible mechanism for improved donor cell survival and reduced immune response following treatment. 

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