Transcriptional landscape of direct reprogramming toward hematopoietic stem cells
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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) offers a promising strategy for generating autologous cells to treat blood and immune disorders. However, low conversion efficiency and incomplete characterization of reprogrammed states limit current protocols. To address this, we assembled a single-cell transcriptomic reference atlas spanning hematopoietic, endothelial, and fibroblast cell types, and evaluated a novel algorithmically predicted transcription factor (TF) recipe—GATA2, GFI1B, FOS, REL, and STAT5A—for induction of HSC-like states. The 5TF recipe increased conversion efficiency of fibroblasts to CD34+ cells by approximately three-fold compared to previous protocols. Long-read single-cell RNA sequencing revealed heterogeneous expression of hematopoietic- and endothelial-associated genes, consistent with partial reprogramming. To benchmark re- programmed cells, we developed an approach to map their transcriptomic positions relative to native and initial cell states within the reference atlas. Finally, we cataloged isoform diversity in reprogrammed cells, suggesting a role for alternative splicing in reprogramming dynamics. These findings highlight both the promise and complexity of direct HSC reprogramming and provide a framework for optimizing future protocols.
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Project description:Reprogramming of mouse fibroblasts toward a myocardial cell fate by forced expression of cardiac transcription factors or microRNAs has recently been demonstrated. The potential clinical applicability of these findings is based on the minimal regenerative potential of the adult human heart and the limited availability of human heart tissue. An initial, but mandatory step toward clinical application of this approach is to establish conditions for conversion of adult human fibroblasts to a cardiac phenotype. Toward this goal, we sought to determine the optimal combination of factors necessary and sufficient for direct myocardial reprogramming of human fibroblasts. Here we show that four human cardiac transcription factors, including Gata4, Hand2, Tbx5, and myocardin, and two microRNAs, miR-1 and miR-133, activated cardiac marker expression in neonatal and adult human fibroblasts. After maintenance in culture for 4-11 weeks, human fibroblasts reprogrammed with these proteins and microRNAs displayed sarcomere-like structures and calcium transients, and a small subset of such cells exhibited spontaneous contractility. These phenotypic changes were accompanied by expression of a broad range of cardiac genes and suppression of non-myocyte genes. These findings indicate that human fibroblasts can be reprogrammed to cardiac-like myocytes by forced expression of cardiac transcription factors with muscle-specific microRNAs and represent a step toward possible therapeutic application of this reprogramming approach. Human foreskin fibroblasts were transduced with 5 transcription factors and total RNA was obtained 4 weeks later. total RNA was also obtained from human foreskin fibroblasts as a negative control and adult human heart tissue as a positive control. The expression level of genes in each sample was compared.
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Project description:Inflammation is a physiopathological process triggered by infection or tissue damage. Immune system initiates coordinated sequential steps in response to these danger signals. Once the threat has been contained inflammation has to be subsequently shut down. Inflammation resolution is initiated by the reprogramming of pro-inflammatory macrophages toward a pro-resolving profile. This reprogramming is induced in particular by the non-phlogistic engulfment of apoptotic cells, mostly apoptotic neutrophils, a process called efferocytosis. As a matter of fact, macrophages are an essential linchpin regulating both inflammation triggering and sustaining and inflammation resolution. This duality can be achieved through the tremendous plasticity of these innate immune cells. Indeed, depending on microenvironmental signals (cytokines, efferocytosis, growth factors…) macrophages can adopt numerous diverse and sometimes antagonistic phenotypes. The mechanisms governing these transitions remain relatively scattered especially in human. With this project we propose to explore the mechanisms involved in human macrophage reprogramming toward a pro-resolving profile after efferocytosis. The stakes are high due to the estimated prevalence of chronic inflammatory diseases in Western society is 5 to 7%. Chronic inflammation is a burden to patient due to life-long debilitating illness and increased mortality and is also a burden to society due to high costs for therapy and care. Finding new therapies to limit chronic inflammation establishment and persistence is thus a highly valuable goal.
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