Spliceosome inhibitor induces human hematopoietic progenitor cell reprogramming toward stemness.

The application of hematopoietic stem cells (HSCs) has been restricted due to limited cell sources and conventional methods for generating these cells by cell expansion and pluripotent stem cell differentiation have not been clinically achieved. Cell reprogramming technique provides a new hope for generating desirable cells. We previously reported that mouse differentiated hematopoietic cell reprogramming could be induced by small molecule compounds to generate hematopoietic stem/progenitor-like cells, whether the human hematopoietic cells could also be reprogrammed into HSCs by chemical compounds remains elusive. Here, we demonstrated for the first time that human committed hematopoietic progenitors could be reprogrammed into multipotent progenitors by spliceosome inhibitor. Combination of single cell RNA-sequencing and genetic lineage tracing including exogenous barcodes and endogenous mitochondrial DNA mutations confirmed the reprogramming procession. Although the small chemical compound inhibiting spliceosome function only induces the differentiated hematopoietic progenitors to acquire plasticity and reprograms them into multipotent progenitors but not stem cells so far, this study still provides a proof-of-concept strategy for generating HSCs based on combining two independent steps together in future, first differentiating rare HSCs into large number of progenitors then reprogramming these progenitors into huge number of HSCs. Further dissecting the mechanism underlying spliceosome inhibitor-induced human hematopoietic cell reprogramming in future will help us comprehensively understanding not only the chemical reprogramming to generate desirable human cells for clinical translation but also hematopoiesis under physiological and pathological conditions.

Neutrophils in cancer carcinogenesis and metastasis.

In recent years, neutrophils have attracted increasing attention because of their cancer-promoting effects. An elevated neutrophil-to-lymphocyte ratio is considered a prognostic indicator for patients with cancer. Neutrophils are no longer regarded as innate immune cells with a single function, let alone bystanders in the pathological process of cancer. Their diversity and plasticity are being increasingly recognized. This review summarizes previous studies assessing the roles and mechanisms of neutrophils in cancer initiation, progression, metastasis and relapse. Although the findings are controversial, the fact that neutrophils play a dual role in promoting and suppressing cancer is undeniable. The plasticity of neutrophils allows them to adapt to different cancer microenvironments and exert different effects on cancer. Given the findings from our own research, we propose a reasonable hypothesis that neutrophils may be reprogrammed into a cancer-promoting state in the cancer microenvironment. This new perspective indicates that neutrophil reprogramming in the course of cancer treatment is a problem worthy of attention. Preventing or reversing the reprogramming of neutrophils may be a potential strategy for adjuvant cancer therapy.

Trajectory of chemical cocktail-induced neutrophil reprogramming.

Hematopoietic reprogramming holds great promise for generating functional target cells and provides new angle for understanding hematopoiesis. We reported before for the first time that diverse differentiated hematopoietic cell lineages could be reprogrammed back into hematopoietic stem/progenitor cell-like cells by chemical cocktail. However, the exact cell types of induced cells and reprogramming trajectory remain elusive. Here, based on genetic tracing method CellTagging and single-cell RNA sequencing, it is found that neutrophils could be reprogrammed into multipotent progenitors, which acquire multi-differentiation potential both in vitro and in vivo, including into lymphoid cells. Construction of trajectory map of the reprogramming procession shows that mature neutrophils follow their canonical developmental route reversely into immature ones, premature ones, granulocyte/monocyte progenitors, common myeloid progenitors, and then the terminal cells, which is stage by stage or skips intermediate stages. Collectively, this study provides a precise dissection of hematopoietic reprogramming procession and sheds light on chemical cocktail-induction of hematopoietic stem cells.