Publications in Cell Stem Cell

Human emotional and stress responses are orchestrated by subcortical limbic circuits, with the amygdala playing a central role in integrating affective, sensory, and endocrine signals. Despite the urgent need to understand how these circuits develop and contribute to anxiety and stress-related disorders, progress has been hindered by lack of ex vivo human models. Here, we generated human amygdala-like telencephalic organoids (hATOs) that recapitulate cellular composition, region-specific development, and key features of the amygdala. By assembling hATOs with a hypothalamic organoid (hypoTO) with paraventricular nucleus (PVN)-like features, we modeled the amygdala-hypothalamus-like interaction, which enabled circuit-level analysis of stress-responsive signaling. Exposure to cortisol led to robust upregulation of BCYRN1, a primate-specific retrotransposon-derived noncoding RNA, which uncovered a previously unrecognized mechanism of stress hormone signaling to retrotransposon biology and human-specific synaptic regulation. These findings highlight the potential of hATOs to understand molecular features of affective circuitry underlying emotion and the stress response and neuropsychiatric disorders.

Human brain organoids provide unique platforms for modeling several aspects of human brain development and pathology. However, current brain organoid systems mostly lack the resolution to recapitulate the development of finer brain structures with subregional identity, including functionally distinct nuclei in the thalamus. Here, we report a method for converting human embryonic stem cells (hESCs) into ventral thalamic organoids (vThOs) with transcriptionally diverse nuclei identities. Notably, single-cell RNA sequencing revealed previously unachieved thalamic patterning with a thalamic reticular nucleus (TRN) signature, a GABAergic nucleus located in the ventral thalamus. Using vThOs, we explored the functions of TRN-specific, disease-associated genes patched domain containing 1 (PTCHD1) and receptor tyrosine-protein kinase (ERBB4) during human thalamic development. Perturbations in PTCHD1 or ERBB4 impaired neuronal functions in vThOs, albeit not affecting the overall thalamic lineage development. Together, vThOs present an experimental model for understanding nuclei-specific development and pathology in the thalamus of the human brain. © 2023 Elsevier Inc.

Heart failure is a leading cause of mortality and morbidity in the developed world, partly because mammals lack the ability to regenerate heart tissue. Whether this is due to evolutionary loss of regenerative mechanisms present in other organisms or to an inability to activate such mechanisms is currently unclear. Here we decipher mechanisms underlying heart regeneration in adult zebrafish and show that the molecular regulators of this response are conserved in mammals. We identified miR-99/100 and Let-7a/c and their protein targets smarca5 and fntb as critical regulators of cardiomyocyte dedifferentiation and heart regeneration in zebrafish. Although human and murine adult cardiomyocytes fail to elicit an endogenous regenerative response after myocardial infarction, we show that in vivo manipulation of this molecular machinery in mice results in cardiomyocyte dedifferentiation and improved heart functionality after injury. These data provide a proof of concept for identifying and activating conserved molecular programs to regenerate the damaged heart.

Since the initial discovery that OCT4, SOX2, KLF4, and c-MYC overexpression sufficed for the induction of pluripotency in somatic cells, methodologies replacing the original factors have enhanced our understanding of the reprogramming process. However, unlike in mouse, OCT4 has not been replaced successfully during reprogramming of human cells. Here we report on a strategy to accomplish this replacement. Through a combination of transcriptome and bioinformatic analysis we have identified factors previously characterized as being lineage specifiers that are able to replace OCT4 and SOX2 in the reprogramming of human fibroblasts. Our results show that it is possible to replace OCT4 and SOX2 simultaneously with alternative lineage specifiers in the reprogramming of human cells. At a broader level, they also support a model in which counteracting lineage specification networks underlies the induction of pluripotency. © 2013 Elsevier Inc.

Finding a cure for cardiovascular disease remains a major unmet medical need. Recent investigations have started to unveil the mechanisms of mammalian heart regeneration. The study of the regenerative mechanisms in lower vertebrate and mammalian animal models has provided clues for the experimental activation of proregenerative responses in the heart. In parallel, the use of endogenous adult stem cell populations alongside the recent application of reprogramming technologies has created major expectations for the development of therapies targeting heart disease. Together, these new approaches are bringing us closer to more successful strategies for the treatment of heart disease. © 2013 Elsevier Inc.