Fig. 2: Correlation of normal human developmental kinetics and its developmental congruence with in vitro hPSC directed differentiation.
Mesoderm. The first wave of human embryonic hematopoiesis begins in the yolk-sac at ~day 19 while self-renewing HSC emerges during the sixth week of gestation in the aorta-gonad-mesonephros (AGM)123. Embryonic hematopoietic waves arise from yolk-sac-like hemangioblast (HB) progenitors after 12 days of in vitro hematopoietic differentiation of hPSC29,30. Yolk sac-like hemogenic endothelium (HE) can similarly be derived via hPSC in vitro differentiation protocols after 15 days of hematopoietic differentiation29,32. Long-term engrafting HSCs similar to those arising from human fetal AGM have not yet been generated via in vitro hPSC differentiation. Endoderm. Pancreatic organoids can be generated in vitro from hPSC with early beta-islet and acinar progenitor cells between 14 and 24 days, and correlate with the emergence of the fetal pancreatic bud at ~day 3051,52. Lung alveolar structures generated in vitro from hPSC after 24 weeks of continuous culture resemble transcriptional phenotypes of fetal lung tissues124,125. Ectoderm retinal cup (RC) and photoreceptor differentiation can be recapitulated in vitro via hPSC-based retinal organoid protocols at ~6 and 17 weeks, respectively, and parallel in vivo retinal developmental events63,126. Post-natal adult neural stem cells emerge in utero in the sub-ventricular zone (SVZ) during week 15 of gestation, and their development can be recapitulated within cerebral organoids, albeit with limited progression to adult neural maturation58,127.
