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: 10531890
• 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/10531890
• 关键词: Allogenic; Blood Vessels; Blood capillaries; Bone Marrow; Bone Surface; Cells; Cellular Stress; Cellular biology; Discontinuous Capillary; Disease; Elements; 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; 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; embryonic stem cell; germline stem cells; hematopoietic stem cell niche; improved; improved outcome; insight; leukemia; leukemic stem cell; neoplasm immunotherapy; novel; novel therapeutic intervention; novel therapeutics; pharmacologic; reconstitution; self-renewal; stem cell biomarkers; stem cell engraftment; stem cell function; stem cell niche; stem cells; stem-like cell; therapy development; therapy resistant; 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.

尽管造血干细胞（HSC）在移植和癌症中已被广泛研究，但HSC小生境的免疫学特性仍在很大程度上未被探索。睾丸和胎盘作为胚胎和生殖系干细胞的免疫避难所，被称为免疫特权部位。在这些组织中，同种异体或异种移植物即使没有免疫抑制治疗也能长期存在。关于组织定向干细胞龛是否具有广泛的免疫特权，人们知之甚少。我们目前的R 01已经测试了骨髓（BM）内的HSC小生境是否作为免疫特权位点，其保护allo-HSC和白血病干细胞（LSC）免受免疫攻击。我们已经证明，明显激活的小生境居住FoxP 3+调节性T细胞（TCFs）使这些HSC免疫豁免。这样的生态位T细胞能够使allo-HSC在非条件免疫活性小鼠中持续存在，同时促进植入。小生境T细胞也屏蔽LSC，导致治疗抗性。为了发现对免疫赦免的进一步基本见解，该R 01更新申请提出了以下研究扩展以表征：A）小生境Tfos; B）高度免疫赦免的、高度原始的HSC/LSC，以及其他干细胞;和C）高度免疫保护性小生境，以及其他HSC小生境位置。关于HSC龛是否位于骨髓窦状隙、小动脉或骨表面一直存在争议。这一争议可能至少部分地解释了HSC的潜在异质性。我们期望免疫赦免识别异质性HSC和小生境内的层级的顶部。该提案将破译小生境TSCs，高度免疫特权的HSC/LSC和高度免疫保护性小生境之间的串扰，并定义它们在allo-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免疫豁免中的关键参与者，以促进allo-HSC植入或克服白血病的治疗耐药性。