Injury to the Spinal Cord Niche Alters the Engraftment Dynamics of Human Neural Stem Cells

Abstract

SummaryThe microenvironment is a critical mediator of stem cell survival, proliferation, migration, and differentiation. The majority of preclinical studies involving transplantation of neural stem cells (NSCs) into the CNS have focused on injured or degenerating microenvironments, leaving a dearth of information as to how NSCs differentially respond to intact versus damaged CNS. Furthermore, single, terminal histological endpoints predominate, providing limited insight into the spatiotemporal dynamics of NSC engraftment and migration. We investigated the early and long-term engraftment dynamics of human CNS stem cells propagated as neurospheres (hCNS-SCns) following transplantation into uninjured versus subacutely injured spinal cords of immunodeficient NOD-scid mice. We stereologically quantified engraftment, survival, proliferation, migration, and differentiation at 1, 7, 14, 28, and 98 days posttransplantation, and identified injury-dependent alterations. Notably, the injured microenvironment decreased hCNS-SCns survival, delayed and altered the location of proliferation, influenced both total and fate-specific migration, and promoted oligodendrocyte maturation.

Transplantation dose alters the dynamics of human neural stem cell engraftment, proliferation and migration after spinal cord injury

“…Endpoints for assessing dynamics of hCNS-SCns survival, proliferation and engraftment were selected based on our previous study describing the effect of SCI niche on hCNS-SCns engraftment between 1 DPT and 14 WPT (Sontag et al 2014). Accordingly, the selected times represent the phases of early engraftment, proliferative expansion in the SCI niche, and the time at which the majority of donor cells have exited the cell cycle and differentiated.…”

“…Understanding the dynamics of donor cell engraftment, proliferation and migration is important for optimizing cell therapies for the injured or diseased CNS. Our recent data indicates that the spinal cord injury (SCI) microenvironment alters the dynamics of transplanted hCNS-SCns when compared to that in uninjured SCI models, suggesting that injury-induced cues and target niche availability play a role in donor cell maturation and migration (Sontag et al 2014). Additionally, donor cells may also secrete factors that serve as extrinsic cues in a dose or density dependent manner.…”

Neutrophils Induce Astroglial Differentiation and Migration of Human Neural Stem Cells via C1q and C3a Synthesis

“…Thirty-micrometer-thick parasagittal sections were cut on a freezing microtome, or 30-mm-thick transverse sections were cut using a CryoJane tape transfer system (Leica), as previously described (35,36). Number of animals cut for each plane is detailed in Table IV.…”

“…CryoJane-cut sections were collected on slides and stored at 220˚C until processed for immunostaining. All sectioning and immunostaining procedures were conducted, as previously described (35,36). Abs and dilutions used are listed in Table II cells, counting areas were determined by drawing contours at every 1-mm region in parasagittal sections using a 34 objective and at a frequency of one every sixth section.…”

Eat, breathe, ROS: controlling stem cell fate through metabolism

“…Research has recently begun to address how the injured microenvironment affects ability of stem cells to proliferate and differentiate. Injured spinal cord delays proliferation and migration of engrafted stem cell neurospheres and alters their differentiation fate [101], while human ESCs are only able to become cardiac precursors in uninjured myocardium [102]. Although research has so far failed to characterize changes to individual cell metabolism following engraftment, one would predict lineage commitment to be inhibited by low oxygen availability.…”