Data-guided direct reprogramming of human fibroblasts into the hematopoietic lineage
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1194990 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31632206_1.fastq.gz | Fastqsanger.gz | |||
| SRR31632207_1.fastq.gz | Fastqsanger.gz | |||
| SRR31632208_1.fastq.gz | Fastqsanger.gz |
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Project description:Direct reprogramming of human fibroblasts into hematopoietic stem cells (HSCs) shows promise for generating autologous cells for treatment of blood and immune-related diseases. However, low conversion efficiency of existing protocols points to gaps in our understanding and opportunities for identification of optimal transcription factor (TF) combinations, which is a major bottleneck for HSC generation. In this study, we tested a novel algorithmically-predicted TF recipe (GATA2, GFIB1, FOS, REL, and STAT5A) for inducing HSC-like states. Our recipe induced CD34+ surface expression and single-cell transcriptomic signatures similar to those of native HSCs. Transcriptional heterogeneity within reprogrammed cells included differences in expression of HSC and endothelial-associated genes and in alternatively spliced transcripts as measured by single-cell long-read RNA-sequencing. Further, we proposed an approach to quantify the relative position of reprogrammed cells within the spectrum of initial and target cell states. This study lays the foundation for efficient optimization of direct reprogramming protocols.
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Project description:Direct lineage conversion holds great promise in the regenerative medicine field for restoring damaged tissues using functionally engineered counterparts. However, current methods of direct lineage conversion, even those employing virus-mediated transgenic expression of tumorigenic factors, are extremely inefficient (~25%). Thus, advanced methodologies capable of revolutionizing efficiency and addressing safety issues are key to clinical translation of these technologies. Here, we propose an exosome-guided, non-viral, direct-lineage conversion strategy to enhance transdifferentiation of fibroblasts to induced cardiomyocyte-like cells (iCMs). Exosomes produced during the cardiac differentiation process of embryonic stem cells (ESCs) are able to achieve extremely high reprogramming efficiency (>60%) by generating functional iCMs from mouse embryonic fibroblasts via a cardiac precursor-like stage rather than a pluripotent state. The resulting iCMs possess typical cardiac Ca2+ transients and electrophysiological features, and exhibit global gene expression profiles similar to those of cardiomyocytes. The optimized reprogramming conditions produce beating iCM clusters ~3-fold more efficiently than conventional methods. This is the first demonstration of the use of exosomes derived from ESCs undergoing cardiac differentiation as biomimetic tools to induce direct cardiac reprogramming with greatly improved efficiency, establishing a general, more readily accessible platform for broadly generating a variety of specialized somatic cells through direct lineage conversion.
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Project description:Direct lineage conversion holds great promise in the regenerative medicine field for restoring damaged tissues using functionally engineered counterparts. However, current methods of direct lineage conversion, even those employing virus-mediated transgenic expression of tumorigenic factors, are extremely inefficient (~25%). Thus, advanced methodologies capable of revolutionizing efficiency and addressing safety issues are key to clinical translation of these technologies. Here, we propose an exosome-guided, non-viral, direct-lineage conversion strategy to enhance transdifferentiation of fibroblasts to induced cardiomyocyte-like cells (iCMs). Exosomes produced during the cardiac differentiation process of embryonic stem cells (ESCs) are able to achieve extremely high reprogramming efficiency (>60%) by generating functional iCMs from mouse embryonic fibroblasts via a cardiac precursor-like stage rather than a pluripotent state. The resulting iCMs possess typical cardiac Ca2+ transients and electrophysiological features, and exhibit global gene expression profiles similar to those of cardiomyocytes. The optimized reprogramming conditions produce beating iCM clusters ~3-fold more efficiently than conventional methods. This is the first demonstration of the use of exosomes derived from ESCs undergoing cardiac differentiation as biomimetic tools to induce direct cardiac reprogramming with greatly improved efficiency, establishing a general, more readily accessible platform for broadly generating a variety of specialized somatic cells through direct lineage conversion.
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Project description:Ultra-Efficient Exosome-Guided Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes
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Project description:Recent reports have shown that somatic cells, under appropriate culture conditions, could be directly reprogrammed to cardiac, hepatic, or neuronal phenotype by lineage-specific transcription factors. In this study, we demonstrate that both embryonic and adult somatic fibroblasts can be efficiently reprogrammed to clonal multilineage hematopoietic progenitors by the ectopic expression of the transcription factors ERG, GATA2, LMO2, RUNX1c, and SCL. These reprogrammed cells were stably expanded on stromal cells and possessed short-term reconstitution ability in vivo. Loss of p53 function facilitated reprogramming to blood, and p53(-/-) reprogrammed cells efficiently generated erythroid, megakaryocytic, myeloid, and lymphoid lineages. Genome-wide analyses revealed that generation of hematopoietic progenitors was preceded by the appearance of hemogenic endothelial cells expressing endothelial and hematopoietic genes. Altogether, our findings suggest that direct reprogramming could represent a valid alternative approach to the differentiation of embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) for disease modeling and autologous blood cell therapies.
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Project description:Direct lineage conversion holds great promise in the regenerative medicine field for restoring damaged tissues using functionally engineered counterparts. However, current methods of direct lineage conversion, even those using virus-mediated transgenic expression of tumorigenic factors, are extremely inefficient (~25%). Thus, advanced methodologies capable of revolutionizing efficiency and addressing safety concerns are key to clinical translation of these technologies. Here, we propose an extracellular vesicle (EV)-guided, nonviral, direct lineage conversion strategy to enhance transdifferentiation of fibroblasts to induced cardiomyocyte-like cells (iCMs). The resulting iCMs have typical cardiac Ca2+ transients and electrophysiological features and exhibit global gene expression profiles similar to those of cardiomyocytes. This is the first demonstration of the use of EVs derived from embryonic stem cells undergoing cardiac differentiation as biomimetic tools to induce cardiac reprogramming with extremely high efficiency (>60%), establishing a general, more readily accessible platform for generating a variety of specialized somatic cells through direct lineage conversion.
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Project description:Direct lineage reprogramming involves the conversion of cellular identity. Single-cell technologies are useful for deconstructing the considerable heterogeneity that emerges during lineage conversion. However, lineage relationships are typically lost during cell processing, complicating trajectory reconstruction. Here we present ‘CellTagging’, a combinatorial cell-indexing methodology that enables parallel capture of clonal history and cell identity, in which sequential rounds of cell labelling enable the construction of multi-level lineage trees. CellTagging and longitudinal tracking of fibroblast to induced endoderm progenitor reprogramming reveals two distinct trajectories: one leading to successfully reprogrammed cells, and one leading to a ‘dead-end’ state, paths determined in the earliest stages of lineage conversion. We find that expression of a putative methyltransferase, Mettl7a1, is associated with the successful reprogramming trajectory; adding Mettl7a1 to the reprogramming cocktail increases the yield of induced endoderm progenitors. Together, these results demonstrate the utility of our lineage-tracing method for revealing the dynamics of direct reprogramming.
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