The current immunooncology artificially ignores the connection with lymphopoiesis, though is only its derivative. Hematopoietic stem cells (HSC) provide physiological regeneration of biomass of the host, fetus, and ma...The current immunooncology artificially ignores the connection with lymphopoiesis, though is only its derivative. Hematopoietic stem cells (HSC) provide physiological regeneration of biomass of the host, fetus, and malignant tumors, as well, as the cells’ reparation after sub-lethally injuring in any tissues and their renewal. HSC, especially of lymphoid lineage, are the most vulnerable of those, which are responsible for viability of organism. Natural and artificial deficits of HSC determine aging, multi-organs syndromes and death of the host, because their current proliferative resource (CPR) is individually limited at birth, and is spending irreversibly during wounds’ healing, pregnancy, tumor growth, and on. CPR, being an integral value of the number of stem cells along the length of their telomeres, is a “shagreen skin”, for which the tumor competes with normal tissues as a quasi-embryonic favorite and winner, especially in the final period of a shortening the life. The primary approach to cancer treatment must prioritize the preservation of CPR remnants, rather than their destruction, in order to temporarily halt the malignant process. The re-targeting of HSC from tumors in favor of normal tissues is the immediate objective of competitive therapy, which allows for preserving the rest of the CPR host’s resources, especially in patients with advanced cancer. However, the contradictory and insignificant practically, the dogma of antitumor cellular immunity continues to dominate and hinder progress in oncology.展开更多
Regeneration of functional B lymphopoiesis from pluripotent stem cells(PSCs)is challenging,and reliable methods have not been developed.Here,we unveiled the guiding role of three essential factors,Lhx2,Hoxa9,and Runx1...Regeneration of functional B lymphopoiesis from pluripotent stem cells(PSCs)is challenging,and reliable methods have not been developed.Here,we unveiled the guiding role of three essential factors,Lhx2,Hoxa9,and Runx1,the simultaneous expression of which preferentially drives B lineage fate commitment and in vivo B lymphopoiesis using PSCs as a cell source.In the presence of Lhx2,Hoxa9,and Runx1 expression,PSC-derived induced hematopoietic progenitors(iHPCs)immediately gave rise to pro/pre-B cells in recipient bone marrow,which were able to further differentiate into entire B cell lineages,including innate B-1a,B-1b,and marginal zone B cells,as well as adaptive follicular B cells.In particular,the regenerative B cells produced adaptive humoral immune responses,sustained antigen-specific antibody production,and formed immune memory in response to antigen challenges.The regenerative B cells showed natural B cell development patterns of immunoglobulin chain switching and hypermutation via cross-talk with host T follicular helper cells,which eventually formed T cell-dependent humoral responses.This study exhibits de novo evidence that B lymphopoiesis can be regenerated from PSCs via an HSC-independent approach,which provides insights into treating B cell-related deficiencies using PSCs as an unlimited cell resource.展开更多
B lymphocytes differentiate from hematopoietic stem cells through a series of distinct stages. Early B cell development proceeds in bone marrow until immature B cells migrate out to secondary lymphoid tissues, such as...B lymphocytes differentiate from hematopoietic stem cells through a series of distinct stages. Early B cell development proceeds in bone marrow until immature B cells migrate out to secondary lymphoid tissues, such as a spleen and lymph nodes, after completion of immunoglobulin heavy and light chain rearrangement. Although the information about the regulation by numerous factors, including signaling molecules, transcription factors, epigenetic changes and the microenvironment, could provide the clinical application, our knowledge on human B lymphopoiesis is limited. However, with great methodological advances, significant progress for understanding B lymphopoiesis both in human and mouse has been made. In this review, we summarize the experimental models for studies about human adult B lymphopoiesis, and the role of microenvironment and signaling molecules, such as cytokines, transforming growth factor-β superfamily, Wnt family and Notch family, with point-by-point comparison between human and mouse.展开更多
Lipopolysaccharide （LPS） is known to be a potent activator of mature B cells by signaling through Toll-like receptor 4 （TLR4）. Its impact on early B-cell development, however, is not well defined. When comparing t...Lipopolysaccharide （LPS） is known to be a potent activator of mature B cells by signaling through Toll-like receptor 4 （TLR4）. Its impact on early B-cell development, however, is not well defined. When comparing to C3H/HeN mice, TLR4-mutant C3H/HeJ mice showed an increase in the number of pro-B and pre-B cells in the bone marrow. When cultured in the presence of IL-7, the proliferation of pro-B and large pre-B cells was significantly inhibited by LPS, possibly due to reduced IL-7 receptor-a （IL-7Ra） expression. Meanwhile, the generation of IgM＋/IgD＋ B cells was greatly enhanced in IL-7 cultures of pro-B and pre-B cells. Consistent with these results, treatment with LPS facilitated the progression of adoptively transferred B220＋IgM-IgD- precursors into IgD＋ cells. Overall, these data suggest that LPS has a profound influence on early B-cell development, which may contribute to the deregulated B-cell development under physiological and pathological conditions such as bacterial infections.展开更多
Laboratory mice have widely been used as tools for basic biological research and models for studying human diseases.With the advances of genetic engineering and conditional knockout(CKO)mice,we now understand hematopo...Laboratory mice have widely been used as tools for basic biological research and models for studying human diseases.With the advances of genetic engineering and conditional knockout(CKO)mice,we now understand hematopoiesis is a dynamic stepwise process starting from hematopoietic stem cells(HSCs)which are responsible for replenishing all blood cells.Transcriptional factors play important role in hematopoiesis.In this review we compile several studies on using genetic modified mice and humanized mice to study function of transcriptional factors in lymphopoiesis,including T lymphocyte and Natural killer(NK)cell development.Finally,we focused on the key transcriptional factor Bcl11b and its function in regulating T cell specification and commitment.展开更多
文摘The current immunooncology artificially ignores the connection with lymphopoiesis, though is only its derivative. Hematopoietic stem cells (HSC) provide physiological regeneration of biomass of the host, fetus, and malignant tumors, as well, as the cells’ reparation after sub-lethally injuring in any tissues and their renewal. HSC, especially of lymphoid lineage, are the most vulnerable of those, which are responsible for viability of organism. Natural and artificial deficits of HSC determine aging, multi-organs syndromes and death of the host, because their current proliferative resource (CPR) is individually limited at birth, and is spending irreversibly during wounds’ healing, pregnancy, tumor growth, and on. CPR, being an integral value of the number of stem cells along the length of their telomeres, is a “shagreen skin”, for which the tumor competes with normal tissues as a quasi-embryonic favorite and winner, especially in the final period of a shortening the life. The primary approach to cancer treatment must prioritize the preservation of CPR remnants, rather than their destruction, in order to temporarily halt the malignant process. The re-targeting of HSC from tumors in favor of normal tissues is the immediate objective of competitive therapy, which allows for preserving the rest of the CPR host’s resources, especially in patients with advanced cancer. However, the contradictory and insignificant practically, the dogma of antitumor cellular immunity continues to dominate and hinder progress in oncology.
基金This work was supported by the National Key R&D Program of China(2019YFA0110203,2020YFA0112404)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010601)+4 种基金the Frontier Science Research Program of the CAS(QYZDB-SSW-SMC057)the Key R&D Program of Guangdong Province(2020B1111470001)the National Natural Science Foundation of China(81925002)the Key Research&Development Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory(2018GZR110104006)the Science and Technology Planning Project of Guangdong Province,China(2020B1212060052).
文摘Regeneration of functional B lymphopoiesis from pluripotent stem cells(PSCs)is challenging,and reliable methods have not been developed.Here,we unveiled the guiding role of three essential factors,Lhx2,Hoxa9,and Runx1,the simultaneous expression of which preferentially drives B lineage fate commitment and in vivo B lymphopoiesis using PSCs as a cell source.In the presence of Lhx2,Hoxa9,and Runx1 expression,PSC-derived induced hematopoietic progenitors(iHPCs)immediately gave rise to pro/pre-B cells in recipient bone marrow,which were able to further differentiate into entire B cell lineages,including innate B-1a,B-1b,and marginal zone B cells,as well as adaptive follicular B cells.In particular,the regenerative B cells produced adaptive humoral immune responses,sustained antigen-specific antibody production,and formed immune memory in response to antigen challenges.The regenerative B cells showed natural B cell development patterns of immunoglobulin chain switching and hypermutation via cross-talk with host T follicular helper cells,which eventually formed T cell-dependent humoral responses.This study exhibits de novo evidence that B lymphopoiesis can be regenerated from PSCs via an HSC-independent approach,which provides insights into treating B cell-related deficiencies using PSCs as an unlimited cell resource.
文摘B lymphocytes differentiate from hematopoietic stem cells through a series of distinct stages. Early B cell development proceeds in bone marrow until immature B cells migrate out to secondary lymphoid tissues, such as a spleen and lymph nodes, after completion of immunoglobulin heavy and light chain rearrangement. Although the information about the regulation by numerous factors, including signaling molecules, transcription factors, epigenetic changes and the microenvironment, could provide the clinical application, our knowledge on human B lymphopoiesis is limited. However, with great methodological advances, significant progress for understanding B lymphopoiesis both in human and mouse has been made. In this review, we summarize the experimental models for studies about human adult B lymphopoiesis, and the role of microenvironment and signaling molecules, such as cytokines, transforming growth factor-β superfamily, Wnt family and Notch family, with point-by-point comparison between human and mouse.
文摘Lipopolysaccharide （LPS） is known to be a potent activator of mature B cells by signaling through Toll-like receptor 4 （TLR4）. Its impact on early B-cell development, however, is not well defined. When comparing to C3H/HeN mice, TLR4-mutant C3H/HeJ mice showed an increase in the number of pro-B and pre-B cells in the bone marrow. When cultured in the presence of IL-7, the proliferation of pro-B and large pre-B cells was significantly inhibited by LPS, possibly due to reduced IL-7 receptor-a （IL-7Ra） expression. Meanwhile, the generation of IgM＋/IgD＋ B cells was greatly enhanced in IL-7 cultures of pro-B and pre-B cells. Consistent with these results, treatment with LPS facilitated the progression of adoptively transferred B220＋IgM-IgD- precursors into IgD＋ cells. Overall, these data suggest that LPS has a profound influence on early B-cell development, which may contribute to the deregulated B-cell development under physiological and pathological conditions such as bacterial infections.
文摘Laboratory mice have widely been used as tools for basic biological research and models for studying human diseases.With the advances of genetic engineering and conditional knockout(CKO)mice,we now understand hematopoiesis is a dynamic stepwise process starting from hematopoietic stem cells(HSCs)which are responsible for replenishing all blood cells.Transcriptional factors play important role in hematopoiesis.In this review we compile several studies on using genetic modified mice and humanized mice to study function of transcriptional factors in lymphopoiesis,including T lymphocyte and Natural killer(NK)cell development.Finally,we focused on the key transcriptional factor Bcl11b and its function in regulating T cell specification and commitment.
