Stem Cell Recruitment of Newly Formed Host Cells via a Successful Seduction? Filling the Gap between Neurogenic Niche and Injured Brain Site

<div><p>Here, we report that a unique mechanism of action exerted by stem cells in the repair of the traumatically injured brain involves their ability to harness a biobridge between neurogenic niche and injured brain site. This biobridge, visualized immunohistochemically and laser captured, corresponded to an area between the neurogenic subventricular zone and the injured cortex. That the biobridge expressed high levels of extracellular matrix metalloproteinases characterized initially by a stream of transplanted stem cells, but subsequently contained only few to non-detectable grafts and overgrown by newly formed host cells, implicates a novel property of stem cells. The transplanted stem cells manifest themselves as pathways for trafficking the migration of host neurogenic cells, but once this biobridge is formed between the neurogenic site and the injured brain site, the grafted cells disappear and relinquish their task to the host neurogenic cells. Our findings reveal that long-distance migration of host cells from the neurogenic niche to the injured brain site can be achieved through transplanted stem cells serving as biobridges for initiation of endogenous repair mechanisms. This is the first report of a stem cell-paved “biobridge”. Indeed, to date the two major schools of discipline in stem cell repair mechanism primarily support the concept of “cell replacement” and bystander effects of “trophic factor secretion”. The present novel observations of a stem cell seducing a host cell to engage in brain repair advances basic science concepts on stem cell biology and extracellular matrix, as well as provokes translational research on propagating this stem cell-paved biobridge beyond cell replacement and trophic factor secretion for the treatment of traumatic brain injury and other neurological disorders. </p> </div

Talactoferrin alfa, a recombinant human lactoferrin promotes healing of diabetic neuropathic ulcers: a phase 1/2 clinical study

Talactoferrin alfa, a recombinant form of human lactoferrin, is a novel immunomodulatory protein with demonstrated ulcer healing properties in animal models. A phase 1/2 clinical study was conducted at 7 clinical sites to determine if talactoferrin can improve wound healing in diabetic patients with foot ulceration. Fifty-five patients with diabetic neuropathic foot ulcers participated in this 2-phase study. In phase 1, groups of 3 patients each received open-label 1%, 2.5%, or 8.5% talactoferrin gel twice daily, in a sequential design, to their ulcer for 30 days. No drug-related adverse events were found at any dose level. Phase 2 was a randomized, placebo-controlled, single-blind study of 2.5% and 8.5% gels, with patients equally divided between the 3 groups. In combination with good wound care, treatment was administered topically twice daily to the ulcers for 12 weeks. The primary endpoint was the incidence of ≥75% healing (relative to baseline size). The study, which in phase 2 was powered to detect a difference between the placebo and combined talactoferrin arms with P < .1, met the primary objective. The groups receiving the 2.5% (n = 15) and 8.5% (n = 15) gels had twice the incidence of ≥75% reduction in ulcer size compared with the placebo group (n = 16): 47%, 53%, and 25%, respectively. On an intent-to-treat basis, the combination of the 2 active groups when compared with the placebo group showed a strong trend toward statistical significance ( P = .09). There were no talactoferrin-related adverse events or laboratory abnormalities. Topical talactoferrin appears to be safe and well tolerated and improves healing of diabetic neuropathic ulcers

Behavioral tests (performed by two investigators blinded to the treatment condition throughout the study) were initially conducted at baseline (i.e., prior to brain insult) and revealed that all adult SD rats included in this study displayed normal behaviors (A, B, and C).

<p>At 7 days after TBI, the same behavioral tests showed that TBI produced significant impairments in motor and neurological tasks. At one month, two months, and three months post-TBI, transplanted animals displayed significantly improved motor and neurological functions compared to traumatically injured animals that received vehicle only. These behavioral improvements were accompanied by reduction in TBI core and peri-injury cell death (D and E) as revealed by H&E staining (a and b correspond to vehicle and transplant respectively at one month post-treatment, while c and d represent vehicle and transplant respectively at three months post-treatment. a-d are at 10X while a’-d’ at 20X magnification). Asterisks (*) indicate significant improvements in behavioral and histological deficits in TBI transplanted cells compared to TBI animals that received vehicle only (p’s < 0.05).</p

Laser-captured biobridge, corresponding to the brain tissue between SVZ and impacted cortex, expressed high levels of MMP-9 gelatinolytic activities at one month and three months post-TBI in animals transplanted with SB623 which were significantly higher than those TBI animals that received vehicle only or sham-operated animals (*p’s< 0.05 vs. vehicle or sham; Panel A).

<p>Although vehicle-infused TBI animals also showed a significantly upregulated MMP-9 gelatinolytic activity at one month post-TBI (**p< 0.05 vs. sham), the level of this neurovascular proteinase activity reverted back to control-sham levels at three months post-TBI. Each bar represents the mean ± standard deviation from n=3 per treatment group for each time point. Next, to further reveal that SB623 cells promoted cell migration via an ECM-mediated mechanism, primary rat cortical cells were either grown alone or co-cultured with SB623 in the presence or absence of the MMP-9 inhibitor Cyclosporine-A (Panel <b>B</b>). Migratory cell assay (see inset) revealed significantly enhanced migration of primary rat cortical cells into the chamber that contained SB623, which was significantly suppressed by treatment with the inhibitor (*p< 0.05 vs. all other treatment conditions). The absence of SB623 and inhibitor in the cell culture condition, the treatment of the inhibitor alone, and the combined treatment of SB623 and inhibitor did not significantly differ in the resulting cell migratory potential.</p

After TBI, endogenous repair mechanisms commenced, but are limited to the neurogenic SVZ and to a few quiescent resident neurogenic cells around the impacted cortex (A).

<p>This endogenous repair process is not sufficient to mount a robust and stable defense against the TBI-induced cell death cascade unless exogenous stem cells are introduced. A physical gap between the neurogenic SVZ and the non-neurogenic, impacted cortex prevents migration of neurogenic cells to the injured cortex. Transplantation of stem cells into the peri-injured cortical areas creates a neurovascular matrix of biobridge to bootleg newly formed endogenous cells from the SVZ to the peri-injured cortex (B). Once the biobridge is established, the endogenous repair mechanism is maintained by newly formed host cells even in the absence of stem cells (C). Such transplant-paved biobridge between neurogenic and non-neurogenic sites allows endogenous neurogenic cells to reach injury-specific brain sites.</p

Stem cell-paved biobridge facilitates neural repair in traumatic brain injury.

Modified mesenchymal stromal cells (MSCs) display a unique mechanism of action during the repair phase of traumatic brain injury by exhibiting the ability to build a biobridge between the neurogenic niche and the site of injury. Immunohistochemistry and laser capture assay have visualized this biobridge in the area between the neurogenic subventricular zone and the injured cortex. This biobridge expresses high levels of extracellular matrix metalloproteinases (MMPs), which are initially co-localized with a stream of transplanted MSCs, but later this region contains only few to non-detectable grafts and becomes overgrown by newly recruited host cells. We have reported that long-distance migration of host cells from the neurogenic niche to the injured brain site can be attained via these transplanted stem cell-paved biobridges, which serve as a key regenerative process for the initiation of endogenous repair mechanisms. Thus, far the two major schools of discipline in stem cell repair mechanisms support the idea of cell replacement and the bystander effects of trophic factor secretion. Our novel observation of stem cell-paved biobridges as pathways for directed migration of host cells from neurogenic niche toward the injured brain site adds another mode of action underlying stem cell therapy. More in-depth investigations on graft-host interaction will likely aid translational research focused on advancing this stem cell-paved biobridge from its current place, as an equally potent repair mechanism as cell replacement and trophic factor secretion, into a new treatment strategy for traumatic brain injury and other neurological disorders

Stem Cell Therapy as an Emerging Paradigm for Stroke (STEPS) II

Cell-based therapies represent a new therapeutic approach for stroke. In 2007, investigators from academia, industry leaders, and members of the National Institutes of Health crafted recommendations to facilitate the translational development of cellular therapies as a novel, emerging modality for stroke from animal studies to clinical trials. This meeting was called Stem Cell Therapies as an Emerging Paradigm in Stroke (STEPS) and was modeled on the format of the Stroke Therapy Academic Industry Roundtable (STAIR) meetings. Since publication of the original STEPS guidelines, there has been an explosive growth in the number of cellular products and in the number of new laboratory discoveries that impact the safety and potential efficacy of cell therapies for stroke. Any successful development of a cell product will need to take into consideration several factors, including the preclinical safety and efficacy profile, cell characterization, delivery route, in vivo biodistribution, and mechanism of action. In 2010, a second meeting called STEPS 2 was held to bring together clinical and basic science researchers with industry, regulatory, and National Institutes of Health representatives. At this meeting, participants identified critical gaps in knowledge and research areas that require further studies, updated prior guidelines, and drafted new recommendations to create a framework to guide future investigations in cell-based therapies for stroke

Stem cells as an emerging paradigm in Stroke 3: enhancing the development of clinical trials

No abstract available