Cell stem cell最新文献

While all eukaryotic cells are dependent on mitochondria for function, in a complex tissue, which cell type and which cell behavior are more sensitive to mitochondrial deficiency remain unpredictable. Here, we show that in the mouse airway, compromising mitochondrial function by inactivating mitochondrial protease gene Lonp1 led to reduced progenitor proliferation and differentiation during development, apoptosis of terminally differentiated ciliated cells and their replacement by basal progenitors and goblet cells during homeostasis, and failed airway progenitor migration into damaged alveoli following influenza infection. ATF4 and the integrated stress response (ISR) pathway are elevated and responsible for the airway phenotypes. Such context-dependent sensitivities are predicted by the selective expression of Bok, which is required for ISR activation. Reduced LONP1 expression is found in chronic obstructive pulmonary disease (COPD) airways with squamous metaplasia. These findings illustrate a cellular energy landscape whereby compromised mitochondrial function could favor the emergence of pathological cell types.

Hematopoietic stem cells (HSCs) employ a very unique metabolic pattern to maintain themselves, while the spectrum of their metabolic adaptations remains incompletely understood. Here, we uncover a distinct and heterogeneous serine metabolism within HSCs and identify mouse HSCs as a serine auxotroph whose maintenance relies on exogenous serine and the ensuing mitochondrial serine catabolism driven by the hydroxymethyltransferase 2 (SHMT2)-methylene-tetrahydrofolate dehydrogenase 2 (MTHFD2) axis. Mitochondrial serine catabolism primarily feeds NAD(P)H generation to maintain redox balance and thereby diminishes ferroptosis susceptibility of HSCs. Dietary serine deficiency, or genetic or pharmacological inhibition of the SHMT2-MTHFD2 axis, increases ferroptosis susceptibility of HSCs, leading to impaired maintenance of the HSC pool. Moreover, exogenous serine protects HSCs from irradiation-induced myelosuppressive injury by fueling mitochondrial serine catabolism to mitigate ferroptosis. These findings reframe the canonical view of serine from a nonessential amino acid to an essential niche metabolite for HSC pool maintenance.

Interspecies blastocyst complementation holds great potential to address the global shortage of transplantable organs by growing human organs in animals. However, a major challenge in this approach is the limited chimerism of human cells in evolutionarily distant animal hosts due to various xenogeneic barriers. Here, we reveal that human pluripotent stem cells (PSCs) struggle to adhere to animal PSCs. To overcome this barrier, we developed a synthetic biology strategy that leverages nanobody-antigen interactions to enhance interspecies cell adhesion. We engineered cells to express nanobodies and their corresponding antigens on their outer membranes, significantly improving adhesion between different species’ PSCs during in vitro assays and increasing the chimerism of human PSCs in mouse embryos. Studying and manipulating interspecies pluripotent cell adhesion will provide valuable insights into cell interaction dynamics during chimera formation and early embryogenesis.

Endogenous retroviruses (ERVs) occupy a significant part of the human genome, with some encoding proteins that influence the immune system or regulate cell-cell fusion in early extra-embryonic development. However, whether ERV-derived proteins regulate somatic development is unknown. Here, we report a somatic developmental function for the primate-specific ERVH48-1 (SUPYN/Suppressyn). ERVH48-1 encodes a fragment of a viral envelope that is expressed during early embryonic development. Loss of ERVH48-1 led to impaired mesoderm and cardiomyocyte commitment and diverted cells to an ectoderm-like fate. Mechanistically, ERVH48-1 is localized to sub-cellular membrane compartments through a functional N-terminal signal peptide and binds to the WNT antagonist SFRP2 to promote its polyubiquitination and degradation, thus limiting SFRP2 secretion and blocking repression of WNT/β-catenin signaling. Knockdown of SFRP2 or expression of a chimeric SFRP2 with the ERVH48-1 signal peptide rescued cardiomyocyte differentiation. This study demonstrates how ERVH48-1 modulates WNT/β-catenin signaling and cell type commitment in somatic development.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic disease. Recent studies have highlighted the persistence of an intermediate state of alveolar stem cells in IPF lungs. In this study, we discovered a close correlation between the distribution pattern of intermediate alveolar stem cells and the progression of fibrotic changes. We showed that amphiregulin (AREG) expression is significantly elevated in intermediate alveolar stem cells of mouse fibrotic lungs and IPF patients. High levels of serum AREG correlate significantly with profound deteriorations in lung function in IPF patients. We demonstrated that AREG in alveolar stem cells is both required and sufficient for activating EGFR in fibroblasts, thereby driving lung fibrosis. Moreover, pharmacological inhibition of AREG using a neutralizing antibody effectively blocked the initiation and progression of lung fibrosis in mice. Our study underscores the therapeutic potential of anti-AREG antibodies in attenuating IPF progression, offering a promising strategy for treating fibrotic diseases.

Macrophages regulate angiogenesis, repair, conduction, and homeostasis in heart tissue. Landau et al.¹ demonstrate that incorporating primitive macrophages into engineered heart tissues significantly promotes long-term vascularization and cardiac maturation. This advance demonstrates the importance of resident immune-vascular microenvironments in cardiac tissue engineering, marking an important step forward for heart-on-chip technologies.

Morphogen gradients are critical regulators of embryonic development. In this issue, Liu et al.¹ introduce a microfluidic system that externally applies morphogen gradients to an in vitro model of human embryo segmentation. It enables the investigation of signaling gradients during this developmental process at unprecedented levels of precision.

Mitrofanova et al.¹ engineer a human colonic in vitro model capable of producing an intestinal mucus barrier, with potential applications for predicting drug-induced gastrointestinal toxicity. This improved system paves the way for more accurate and efficient drug development processes.

Yang et al.¹ generate tissue engineered blood vessels from hiPSC-derived smooth muscle cells harboring a mutation found in Loeys-Dietz syndrome. In vitro and in vivo data from these vessels provide new insight into the molecular physiology of aortic aneurysms and may create a paradigm for understanding a suite of vascular diseases.