Intravenous Grafts Recapitulate the Neurorestoration Afforded by Intracerebrally Delivered Multipotent Adult Progenitor Cells in Neonatal Hypoxic-Ischemic Rats

Abstract

Once hypoxic-ischemic (HI) injury ensues in the human neonate at birth, the resulting brain damage lasts throughout the individual's lifetime, as no ameliorative treatments are currently available. We have recently shown that intracerebral transplantation of multipotent adult progenitor cells (MAPCs) results in behavioral improvement and reduction in ischemic cell loss in neonatal rat HI-injury model. In an attempt to advance this cellular therapy to the clinic, we explored the more practical and less invasive intravenous administration of MAPCs. Seven-day-old Sprague-Dawley rats were initially subjected to unilateral HI injury, then 7 days later received intracerebral or intravenous injections of allogeneic rat MAPCs. On post-transplantation days 7 and 14, the animals that received MAPCs via the intracerebral or intravenous route exhibited improved motor and neurologic scores compared with those that received vehicle infusion alone. Immunohistochemical evaluations at day 14 after transplantation revealed that both intracerebrally and intravenously transplanted MAPCs were detected in the ischemic hippocampal area. The degree of hippocampal cell preservation was almost the same in the two treatment groups and greater than that in the vehicle group. These results show that intravenous delivery of MAPCs is a feasible and efficacious cell therapy with potential for clinical use.

Mesenchymal stem cells as a treatment for neonatal ischemic brain damage

“…Intracranial injection of MSCs after neonatal ischemic brain injury in rodents improved functional recovery and reduced lesion size (27)(28)(29). Moreover, MSCs transplanted via the intravenous or intracardiac route also improved functional recovery (26,30). To circumvent the invasive procedure of local intracranial administration and the loss of cells after peripheral administration, we studied the possibility of using the intranasal administration route (31).…”

“…It could be argued that migration of MSCs to the lesion site allows for a better adaptation of MSCs to the harsh ischemic environment, leading to better MSC survival than after intracranial transplantation early after transplantation. However, the number of MSCs surviving up to 4 wk after intracranial, intravenous, intracardiac, and intranasal transplantation is less than 1% (26,30,32,41), so the administration route has little to no influence on late graft survival. This number of surviving cells remains small in relation to the lesion volume and the number of MSCs that may integrate into the cerebral network is too little to cause the impressive effects just by mere differentiation of transplanted MSCs.…”

Rescuing the neonatal brain from hypoxic injury with autologous cord blood

“…14,17,[61][62][63][64][65] MSCs, which can also be isolated from BM and other sources, have been demonstrated to exert neuro-protection in HIE animal models. [66][67][68][69][70] Cell lines with NSC properties have been established from HUCB following immune-depletion of the CD34-positive cells from CB and spontaneous aggregation and differentiation with stimulation by epithelial growth factor. 71 When such CB-NSCs were seeded on human-originated biodegradable scaffold, they were able to differentiate into neurons, form functional circuits and generate spontaneous field/action potentials.…”

“…104,[107][108][109][110] Route of stem cell administration Migration of various types of stem cells to the site of injury has been documented in HIE animal studies following either systematic or local injection. 70,84,111,112 Considering the volume of CB and the young age of the neonates with HIE, i.v. infusion is a safe and effective method of administration, even though it means that only a limited number of cells may arrive in the damaged brain.…”

“…injection. 70 Meanwhile, the safety of such an invasive procedure has to be carefully evaluated before its application in clinical studies.…”