Transplantation of iPS‐derived vascular endothelial cells improves white matter ischemic damage

Abstract

White matter infarct induces demyelination and brain dysfunction. We previously reported that transplantation of brain microvascular endothelial cells improved the behavioral outcome and promoted remyelination by increasing the number of oligodendrocyte precursor cells in the rat model of white matter infarct. In this study, we investigated the effects of transplantation of vascular endothelial cells generated from human induced pluripotent stem cells (iPSCs) on the rat model of white matter infarct. Seven days after induction of ischemic demyelinating lesion by injection of endothelin‐1 into the internal capsule of a rat brain, iPSC‐derived vascular endothelial cells (iVECs) were transplanted into the site of demyelination. The majority of iVECs transplanted into the internal capsule survived for 14 days after transplantation when traced by immunohistochemistry for a human cytoplasmic protein. iVEC transplantation significantly recovered hind limb rotation angle as compared to human iPSC or rat meningeal cell transplantation when evaluated using footprint test. Fourteen days after iVEC transplantation, the infarct area remarkably decreased as compared to that just before the transplantation when evaluated using magnetic resonance imaging or luxol fast blue staining, and remyelination was promoted dramatically in the infarct when assessed using luxol fast blue staining. Transplantation of iVECs increased the number of oligodendrocyte lineage cells and suppressed the inflammatory response and reactive astrocytogenesis. These results suggest that iVEC transplantation may prove useful in treatment for white matter infarct.

Efficacy of a cultured conditioned medium of exfoliated deciduous dental pulp stem cells in erectile dysfunction patients

“…Research into regenerative medicine, in which stem cells including induced pluripotent stem (iPS) cells and embryonic stem (ES) cells are transplanted, is drawing attention as a new treatment for central nervous system diseases such as cerebral infarction and spinal cord injury. 12 , 13 However, there are many problems with stem cell transplantation, such as hazardous immune rejection against allografts and potential oncogenetic risk as well as complicating process of preservation and culture methods of iPS/ES cells. 14 , 15 , 16 Recently, various studies have demonstrated that culture supernatants of stem cells possess ability of repairing damaged tissues, protect tissues, and ultimately regenerate organs with utilizing their own stem cells in situ .…”

Transplanted human iPSC-derived vascular endothelial cells promote functional recovery by recruitment of regulatory T cells to ischemic white matter in the brain

“…iVEC differentiation from human iPSCs was performed according to previously described [ 11 ]. Briefly, iPSCs were singularized with Accutase (Millipore, Cat# SCR005) and seeded on growth factor-reduced Matrigel-coated 6-well plate at a density of 10,000 cells/cm 2 .…”

“…Our previous reports showed transplantation of rat brain microvascular endothelial cells and human induced pluripotent stem cell (iPSC)-derived vascular endothelial cells (iVECs) improves locomotor deficit, reduces infarct area, promotes remyelination, and suppresses neuroinflammation [ 10 , 11 ]. We also showed that transplantation of vascular endothelial cells into the infarct area promotes increase of oligodendrocyte precursor cells (OPCs) in the region [ 12 ].…”

Applying hiPSCs and Biomaterials Towards an Understanding and Treatment of Traumatic Brain Injury

“…The tight dependence of WM on the vascular system requires that reparative therapies integrate a multifactorial approach that counters endothelial dysfunction and inflammation, since oligodendrogenesis may not be sufficient to fully restore WM fibers (Hamanaka et al, 2018). Indeed, transplantation of hiPSC-derived endothelial cells (ECs) within demyelinated areas has been shown to form functional vessels in a mouse model of WM ischemic infarct (Xu et al, 2019). Transplantation of ECs enhanced cell survival, increased the number of OPCs, suppressed inflammatory responses and astrocytosis, decreased the ischemic area, promoted remyelination, and recovered limb coordination.…”