Combination therapy of stem cell derived neural progenitors and drug delivery of anti-inhibitory molecules for spinal cord injury

Abstract

Regeneration of lost synaptic connections following spinal cord injury (SCI) is limited by local ischemia, cell death, and an excitotoxic environment, which leads to the development of an inhibitory glial scar surrounding a cystic cavity. While a variety of single therapy interventions provide incremental improvements to functional recovery after SCI, they are limited; a multifactorial approach that combines several single therapies may provide a better chance of overcoming the multitude of obstacles to recovery. To this end, fibrin scaffolds were modified to provide sustained delivery of neurotrophic factors and anti-inhibitory molecules, as well as encapsulation of embryonic stem cell-derived progenitor motor neurons (pMNs). In vitro characterization of this combination scaffold confirmed that pMN viability was unaffected by culture alongside sustained delivery systems. When transplanted into a rat sub-acute SCI model, fibrin scaffolds containing growth factors (GFs), anti-inhibitory molecules without pMNs, or pMNs with GFs had lower chondroitin sulfate proteoglycan levels compared to scaffolds containing anti-inhibitory molecules with pMNs. Scaffolds containing pMNs, but not anti-inhibitory molecules, showed survival, differentiation into neuronal cell types, axonal extension in the transplant area, and the ability to integrate into host tissue. However, the combination of pMNs with sustained-delivery of anti-inhibitory molecules led to reduced cell survival and increased macrophage infiltration. While combination therapies retain potential for effective treatment of SCI, further work is needed to improve cell survival and to limit inflammation.

Insight on stem cell preconditioning and instructive biomaterials to enhance cell adhesion, retention, and engraftment for tissue repair

“…Examination after 2 weeks revealed the survival of transplanted cells (as assessed using robust GFP þ expression); however, groups containing pMNs showed less cell survival, possibly due to an enhanced inflammatory response within the lesion site. Moreover, transplanted pMNs differentiated into neurons and oligodendrocytes, bridged the injury site, and extended axonal projections within the transplant area [283]. However, studying the long-term effects of the combination therapies on functional recovery is important to understand that how the transplants are incorporating into the host tissue.…”

“…The combined delivery of cells, neurotrophic factors, and anti-inhibitory molecules (AIMS) may lead to improved recovery as compared to any single treatment alone. To this end, Wilems et al simultaneously delivered PDGF-BB, NT-3, AIMS, and ESCs-derived pMNs in an SCI model 2 weeks after injury [283]. Animals received of the following treatment: 1) fibrin þ growth factors (GFs), 2) fibrin þ GFs þ pMNs, 3) fibrin þ AIMS, 4) fibrin þ AIMS þ pMNs, and 5) fibrin þ AIMS þ GFs þ pMNs.…”

Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?

“…While combined treatment approaches are also utilized in other central nervous system disorders, such as stroke (Gisvold et al, 1984; Liu et al, 2010; Wang et al, 2012; Ji et al, 2015; Schuch et al, 2016) and spinal cord injury (Koopmans et al, 2009; Tanabe et al, 2009; Lee et al, 2012; Wilems et al, 2015), the aim of this review is to highlight the current state of combinational treatment approaches for neurobehavioral and cognitive recovery in experimental TBI. The review, which is the first, and currently the only, to comprehensively assess the effects of combination therapies on behavioral outcomes after TBI, is based on studies that were found on a PubMed search in March 2016 using the key phrase “combination AND therapy AND traumatic AND brain AND injury” that produced 529 papers.…”

Neurotrophic Factors Used to Treat Spinal Cord Injury

“…NT-3 has also been administered in a range of studies in association with scaffolds of various types, composed of collagen Houweling, van Asseldonk, et al, 1998;Li et al, 2016;Yao et al, 2013), fibrin (Guo et al, 2007;Taylor, Jones, et al, 2006;Wilems et al, 2015), matrigel (Bamber et al, 2001), hyaluronic acid/PLGA (Wen et al, 2015), chitosan , or hydrogels (Piantino et al, 2006;Tsai et al, 2006). Improved outcomes using a combination of NT-3 gradients, peripheral conditioning lesions, and stromal cell grafts up to 15 months after SCI have also been reported (Kadoya et al, 2009).…”

“…This neurotrophin has also been extensively used in experimental SCI studies (Table 1) and occasionally in studies that compare delivery of NT-3 to the effects of BDNF in the same lesion paradigm (Bamber et al, 2001;Boyce et al, 2012;Brock et al, 2010;Iarikov et al, 2007;Li et al, 2016;Lynskey et al, 2006;McTigue et al, 1998;Novikova et al, 2000;Ollivier-Lanvin et al, 2014;Piantino et al, 2006;Ruitenberg et al, 2003;Schnell et al, 1994;Taylor, Jones, et al, 2006;Tuinstra et al, 2012;Wilems et al, 2015;Xu et al, 1995;Yick et al, 1999) (see also Table 1). Most experiments involve mid-to-low thoracic injuries, although several cervical SCI studies have been undertaken (Alto et al, 2009;Brock et al, 2010;Fouad et al, 2013;Gunther et al, 2015;Hagg et al, 2005;Hou et al, 2012;Iarikov et al, 2007;Kadoya et al, 2009;Lu et al, 2007;Lynskey et al, 2006;Novikova et al, 2000;Ruitenberg et al, 2005Ruitenberg et al, , 2003Taylor, Jones, et al, 2006).…”