Granted Patent
B2
US 12,618,044 · App. 18/069,299 · Granted May 5, 2026
Specification of functional cranial placode derivatives from human pluripotent stem cells
Inventors:
Stuart Chambers (San Francisco, CA); Lorenz Studer (New York, NY); Zehra Dincer (New York, NY); Bastian Zimmer (Hamburg, DE)
Assignee:
MEMORIAL SLOAN-KETTERING CANCER CENTER
C12N5/0619A61K35/12C07D211/00C07D243/36C07D307/32C12N2501/119C12N2501/13C12N2501/155C12N2501/41C12N2501/415C12N2501/727C12N2501/734C12N2501/998C12N2501/999C12N2506/02C12N2506/45
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Abstract
Cranial placodes are embryonic structures essential for sensory and endocrine organ development. The efficient derivation of cranial placodes from human pluripotent stem cells is disclosed where the timed removal of the BMP inhibitor Noggin, a component of the dual-SMAD inhibition strategy of neural induction, triggers placode induction at the expense of CNS fates. Further fate specification at the pre-placode stage enables the selective generation of placode-derived trigeminal ganglia capable of in vivo engraftment, mature lens fibers and anterior pituitary hormone-producing cells that upon transplantation produce hormones including, but not limited to, human growth hormone and adrenocortiocotropic hormone in vivo. Alternatively, anterior pituitary hormone-producing cells are generated in cell culture systems in vitro.
Claims (11)
1 . A method for inducing differentiation of cells, comprising:
a) contacting a plurality of cells with an inhibitor of Small Mothers Against Decapentaplegic protein signaling (“SMAD inhibitor”) and a bone morphogenetic protein (“BMP”) in amounts effective to induce detectable expression of SIX1 and PAX6 in the plurality of cells;
b) contacting the cells expressing detectable levels of SIX1 and PAX6 with an activator of Wnt signaling in an amount effective to obtain differentiated cells expressing detectable levels of SIX1 and PAX3; and
c) culturing the cells expressing SIX1 and PAX3 under conditions favoring differentiation of cells expressing SIX1 and PAX3 into trigeminal neurons.
2 . The method of claim 1 , wherein the method comprises contacting the cells with the SMAD inhibitor for up to about 11 days, and wherein the cells are contacted with the BMP for up to about 3 days.
3 . The method of claim 1 , wherein the cells expressing SIX1 and PAX3 are trigeminal placode cells.
4 . The method of claim 3 , wherein the cells expressing SIX1 and PAX3 further express a detectable level of GD2, CD57, or a combination thereof.
5 . The method of claim 4 , further comprising isolating the cells expressing a detectable level of GD2, CD57, or a combination thereof from the plurality of cells.
6 . The method of claim 1 , further comprising contacting the cells with a compound selected from the group consisting of BRL-54443, parthenolide, phenantroline, and combinations thereof.
7 . The method of claim 1 , wherein the cells expressing SIX1 and PAX6 further express a detectable level of TFAP2A.
8 . The method of claim 1 , wherein the conditions favoring differentiation of cells expressing SIX1 and PAX3 into trigeminal neurons comprise exposing the cells to at least one of brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and DAPT.
Continuity (5)
Continuation
PCTUS2014066952
· Nov 21, 2014
Provisional Application
61907302
· Nov 21, 2013
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