Privileged and primitive hematopoietic stem cells, niches, and regulatory T cells

特权和原始造血干细胞、生态位和调节性 T 细胞

• 批准号: 10364110
• 负责人: Joji Fujisaki
• 金额: $ 77.41万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364110
• 关键词: Allogenic; Biology; Blood Vessels; Blood capillaries; Bone Marrow; Bone Surface; Cells; Cellular Stress; Discontinuous Capillary; Disease; Elements; Embryo; Engraftment; Exhibits; FOXP3 gene; Fingerprint; Genes; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Heterogeneity; Image; Immune; Immunocompetent; Immunologics; Link; Location; Malignant - descriptor; Malignant Neoplasms; Molecular Profiling; Mus; Nitric Oxide; Pharmacology; Placenta; Population; Predisposition; Property; RNA; Regulation; Regulatory T-Lymphocyte; Relapse; Resistance; Role; Signal Transduction; Site; Stem cell transplant; Stress; T-cell receptor repertoire; Testing; Testis; Tissues; Transplantation; arteriole; cancer cell; cancer stem cell; cancer therapy; germline stem cells; hematopoietic stem cell niche; improved; improved outcome; insight; leukemia; leukemic stem cell; neoplasm immunotherapy; novel; novel therapeutic intervention; novel therapeutics; reconstitution; self-renewal; stem cell biomarkers; stem cell engraftment; stem cell function; stem cell niche; stem cells; stem-like cell; therapy development; therapy resistant; tissue stem cells; transcriptome sequencing

Although hematopoietic stem cells (HSCs) have been extensively studied in transplantation and cancer, immunological properties of the HSC niche have remained largely unexplored. The testis and placenta act as immunological sanctuaries for embryonic and germline stem cells, and are termed immune privileged sites. In these tissues, allogeneic (allo-) or xenogeneic grafts persist long-term, even without immune suppressive therapy. Little is known about whether tissue-committed stem cell niches are broadly immune privileged. Our current R01 has tested whether the HSC niche within the bone marrow (BM) acts as an immune privileged site that shields both allo-HSCs and leukemic stem cells (LSCs) from immune attack. We have demonstrated that distinctly activated niche-residential FoxP3+ regulatory T cells (Tregs) render such HSCs immune privileged. Such niche Tregs enable the persistence of allo-HSCs in non-conditioned immune competent mice, while promoting engraftment. Niche Tregs also shield LSCs, leading to therapeutic resistance. To discover further fundamental insights into immune privilege, this R01 renewal application proposes the following extensions of study to characterize: A) niche Tregs; B) highly immune-privileged, highly primitive HSCs/LSCs, amongst other stem cells; and C) highly immunoprotective niches, amongst other HSC niche locations. There has remained a long-standing controversy as to whether the HSC niche localizes at BM sinusoids, arterioles, or the bone surface. This controversy may be at least partially explained by potential heterogeneity in HSCs. We expect that immune privilege identifies the top of the hierarchy within heterogenous HSCs and niches. The proposal will decipher the crosstalk among niche Tregs, highly immune-privileged HSCs/LSCs, and highly immunoprotective niches, and define their roles in allo-HSC transplantation and in leukemia. Our wok will further develop new therapies to manipulate or transfer these linked key players in immune privilege to promote allo-HSC engraftment or to overcome therapeutic resistance in leukemia.

虽然造血干细胞（HSC）已经在移植和癌症中得到了广泛的研究，但HSC生态位的免疫学特性在很大程度上仍未被探索。睾丸和胎盘作为胚胎和种系干细胞的免疫庇护所，被称为免疫特权部位。在这些组织中，即使没有免疫抑制治疗，同种异体（allo-）或异种移植物也能长期存在。对于组织承诺的干细胞壁龛是否具有广泛的免疫特权，人们知之甚少。我们目前的R01测试了骨髓（BM）内的HSC生态位是否作为一个免疫特权位点，保护同种异体HSC和白血病干细胞（LSCs）免受免疫攻击。我们已经证明，明显激活的小生境FoxP3+调节性T细胞（Tregs）使这些造血干细胞具有免疫特权。这种小生境Tregs使同种造血干细胞在非条件免疫能力小鼠体内持续存在，同时促进移植。小生境Tregs也会保护LSCs，导致治疗耐药性。为了进一步发现免疫特权的基本见解，本R01更新申请提出以下研究扩展以表征：A)生态位Tregs；B)高度免疫特权、高度原始的造血干细胞/LSCs，以及其他干细胞；C)高度免疫保护的生态位，在其他HSC生态位中。关于HSC的生态位是位于基底动脉窦、小动脉还是骨表面，一直存在着长期的争议。造血干细胞的潜在异质性至少可以部分解释这一争议。我们期望免疫特权在异质造血干细胞和小生境中识别层次结构的顶端。该建议将破译生态位treg、高度免疫特权的hsc /LSCs和高度免疫保护的生态位之间的串扰，并确定它们在同种异体hsc移植和白血病中的作用。我们的工作将进一步开发新的疗法来操纵或转移这些与免疫特权相关的关键参与者，以促进同种异体造血干细胞的植入或克服白血病的治疗耐药性。