Purification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1

Abstract

Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (mDA) neurons for cell replacement therapy for Parkinson's disease (PD). However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate cells. To eliminate these unwanted cells, cell sorting using antibodies for specific markers such as CORIN or ALCAM has been developed, but neither marker is specific for ventral midbrain. Here we employ a double selection strategy for cells expressing both CORIN and LMX1A::GFP, and report a cell surface marker to enrich mDA progenitors, LRTM1. When transplanted into 6-OHDA-lesioned rats, human iPSC-derived LRTM1+ cells survive and differentiate into mDA neurons in vivo, resulting in a significant improvement in motor behaviour without tumour formation. In addition, there was marked survival of mDA neurons following transplantation of LRTM1+ cells into the brain of an MPTP-treated monkey. Thus, LRTM1 may provide a tool for efficient and safe cell therapy for PD patients.

Three-dimensional induction of dorsal, intermediate and ventral spinal cord tissues from human pluripotent stem cells

“…Histological studies of mouse embryonic tissues were performed as previously described (Samata et al, 2016). Pregnant mice (C57BL/6NCrSlc) were obtained from Shimizu Laboratory Supplies (Kyoto, Japan).…”

Induced pluripotent stem cells in rat models of Parkinson's disease: A systematic review and meta‑analysis

“…For amphetamine-induced rotational tests, data from six studies (16,17,20,21,23,25) were reported. One study (21) used two different iPSC lines, and had separate control group and outcomes.…”

“…For apomorphine-induced rotation tests, similarly, one study (24) was excluded from the pooled analysis due to the data being represented in the form of a ratio and one study (16) did not describe the outcome in detail; therefore, it was not possible to calculate the mean and SD. Thus only three experiments (21,25) were reported for evaluating the effect of iPSCs on apomorphine-induced rotation tests. The outcome used the fixed-effects model and indicated that iPSCs also improved the apomorphine-induced rotation tests (SMD, -1.45; 95% CI, -2.16 to -0.73; P<0.00001; heterogeneity: χ 2 =1.07, P=0.59, I 2 =0%; Fig.…”

“…By reading the full text of the remaining 125 articles carefully, 16 studies were excluded due to not having unsorted iPSC experiments; 28 studies were excluded because there was no PD model; 54 were excluded because in vivo testing had not been performed; 12 studies were removed because the animal model was impertinent; and one was published after March 2017. Therefore, eight studies (16,17,(20)(21)(22)(23)(24)(25) met the eligibility criteria and were included in the meta-analyses. The systematic search to identify all articles for the meta-analysis is presented in Fig.…”

Evidence brings hope for high‐yield dopaminergic human‐induced pluripotent stem cell transplant

“…Human‐induced pluripotent stem cells (hiPSCs) can provide a source for midbrain dopaminergic (mDA) neurons for cell therapy in Parkinson's disease. The pitfalls to this method are the remaining tumorigenic progenitors and contamination with mature cell types . Samata and colleagues introduce LRTM1—a novel cell‐surface marker expressed in the ventral midbrain (VM)—and provide evidence that by using anti‐LRTM1 antibodies, isolated mDA progenitors are able to differentiate into mature mDA neurons and produce eye‐catching clinical results.…”