Investigating the role of CD44 and immune-neuro signaling mechanisms in neural stem cell responses after spinal cord injury

Project Summary
Spinal cord injury (SCI) results in long-term functional impairments due to loss of cord tissue and limited
regeneration. Human neural stem cell (hNSC) transplantation has exciting potential as a treatment for
SCI, but the complex interactions between hNSC and the extrinsic microenvironment are poorly
understood. The objective of this proposal is to address this gap in knowledge, enabling both optimization
of therapeutic donor hNSC transplantation, as well as new insights into in vivo signaling/transcriptional
networks, and the consequence of these networks for hNSC localization and fate after SCI. Critical to this
is goal is elucidating mechanisms of immune-NSC signaling.
Spinal Cord Injury (SCI) causes disruption of the blood-spinal-cord barrier, and a robust influx of serum
proteins, including C1q. SCI also results in a multiphasic and prolonged immune response, in which
infiltrating and resident immune cells also secrete C1q. We have shown that C1q influx is chemoattractive
for transplanted hNSC, inducing hNSC migration towards and clustering at the injury epicenter, and driving
hNSC towards an astroglial lineage. Blockade of C1q in vivo releases both migration and lineage selection,
and enhances SCI repair and locomotor recovery. We have also shown that C1q directly modulates hNSC
migration, proliferation, and differentiation in vitro via a receptor-mediated signaling mechanism. Using an
unbiased screen, we identified novel interactions between C1q and five candidate receptors expressed by
hNSC. Among these is CD44, a receptor with an established role in regulating cellular behavior. Our
published data identify CD44 as a principal mediator of hNSC chemoattraction to C1q in vitro and in vivo,
and show that C1q-CD44 signaling also modulates hNSC fate. Further, CD44 deletion in hNSC in an acute
transplantation paradigm in vivo enhances SCI repair and locomotor recovery.
The central hypotheses of the proposed aims are that C1q-CD44 signaling in NSC alters the NSC
transcriptome via CD44-ICD heterochromatin modulation, and that deletion of CD44 in transplanted hNSC
after SCI will enhance repair. Aim 1 investigates the effect of CD44 KO on hNSC gene expression at
baseline and in response to the CD44 ligands C1q, HA, and osteopontin. Aim 2 tests the effect of CD44
deletion on the repair capacity of hNSC transplanted into the SCI microenvironment, and the dependence
of this effect on C1q. Aim 3 investigates the effect of CD44 KO in hNSC on localization and fate in relation
to signaling and transcriptional networks in vivo after SCI

Grant Number: 5R01NS123927-04
NIH Institute/Center: NIH
Principal Investigator: Aileen Anderson