Biology Reference
In-Depth Information
Some aspects specific for this approach have to be addressed. A charac-
terization of grafted cells preclinically (cell migration, survival) was
completely missing. Details of the grafting procedure were not evaluated
systematically in the preclinical setting (location of injected cells, visualiza-
tion of damaged cord prior to grafting). The interpretation of behavioral data
(BBB locomotor score), which represented a key element in assessing the
therapeutic potential of this strategy, needs to be discussed.
1.2. Embryonic stem cells
The loss of oligodendrocytes at the lesion as well as rostral and caudal to the
lesion site, resulting in demyelination and loss of appropriate nerve conduc-
tion, significantly contributes to functional deficits after SCI (
Crowe,
Bresnahan, Shuman, et al., 1997; Gledhill, Harrison, & McDonald, 1973;
Hulsebosch, 2002
). Clinical assessment and postmortem morphological
studies in SCI individuals indicate that a preserved rim of spared axons
frequently exists even in motor complete SCI (
Kakulas, 1999; Sherwood,
Dimitrijevic, & McKay, 1992
). The majority of these spared axons was
found to be demyelinated (
Kakulas, 1999
). The adult spinal cord exhibits
only a limited intrinsic capacity for oligodendroglial replacement and
remyelination. In particular, the terminal differentiation of oligodendroglial
precursor cells into mature myelinating oligodendrocytes is insufficient
(
Levine & Reynolds, 1999
). Therefore, regenerative strategies aiming to
replace myelinating oligodendrocytes represent one potential means
to
promote recovery even in functionally complete SCI patients.
The group around Hans Keirstead differentiated hESCs of the H7 hESC
line into oligodendrocyte progenitor cells (OPC) of high purity (
Keirstead
et al., 2005
). Two lakhs and fifty thousand enriched OPCwere grafted 7 days
after a moderate or severe thoracic contusion SCI 4 mm caudal and rostral to
the “lesion epicenter.” The “lesion epicenter” was not further specified. The
grafted OPC differentiated into mature adenomatous polyposis coli (APC)
expressing oligodendrocytes. The total number of axons remyelinated by ol-
igodendrocytes and Schwann cells increased by 136%. Grafted OPC
accounted for 55% of axon remyelination. OPC grafting elicited locomotor
improvement (around 17 on the BBB locomotor scale
¼
“frequent to con-
sistent weight supported plantar steps and frequent FL-HL coordination”
compared to around 13 in medium injected control animals
¼
“consistent
plantar stepping and consistent FL-HL coordination during gait”; four-
parameter kinematic analysis). OPC grafting into the chronically injured
