The synergistic effect of NOTCH, SALL4, and hydrogel on hematopoietic stem cells

描述(申请人提供)：造血干细胞(HSCs)是一种罕见的干细胞，具有分化为特殊血细胞的能力，包括淋巴细胞、红血球细胞和血小板。造血干细胞被用于临床移植治疗各种疾病，包括白血病、血液和免疫系统的先天异常、再生障碍性贫血和血红蛋白疾病。然而，寻找匹配的捐赠者是困难的、耗时的，对于非裔美国人、西班牙裔美国人、美洲原住民和混合种族的人来说尤其困难。目前，只有三分之一的患者能找到合适的捐献者；因此，许多患者在找到合适的配型之前就去世了。虽然在过去的30年里，成功扩增这些细胞的研究已经持续了很长时间，但目前还没有一种常规的方法来体外扩增人类造血干细胞，在临床应用中取得的成功也有限。 我们假设内在因素和外在因素在获得合适的造血干细胞/造血祖细胞(造血祖细胞)群体以获得成功的骨髓移植中起着关键作用。如果成功，拟议的创新方法将有可能改变骨髓移植领域，并为患有血液病、免疫缺陷疾病和再生障碍性贫血等多种疾病的患者提供治疗选择。我们提议的具体目标集中在实现这一目标上。目的1.确定ICD-NOTCH和水凝胶细胞外基质在促进人脐血(HUCB)定向扩增HSC/HPC方面是否具有协同作用。目的2.比较联合应用ICD-Noch、SALL4和水凝胶细胞外基质扩增人脐血是否能提高短期和长期再集落对骨髓恢复的效率。

DESCRIPTION (provided by applicant): Hematopoietic stem cells (HSCs) are rare stem cells that have the ability to differentiate into specialized blood cells, including lymphocytes, red blod cells, and platelets. HSCs are used in clinical transplantation protocols to treat a variety of diseases, including leukemia, inborn anomalies of the blood and immune system, aplastic anemia, and hemoglobinopathies. However, finding a matching donor is difficult, time consuming, and especially problematic for African Americans, Hispanics, Native Americans, and people of mixed ethnicity. Currently, only 1 in 3 patients will find a suitable donor; thus, many patients die before finding an appropriate match. While studies to successfully expand these cells have spanned over the last three decades, a routine method for ex vivo expansion of human HSCs is still not available and has been met with limited success for clinical applications. We hypothesize that both intrinsic and extrinsic factors play key roles in obtaining a suitable population of HSCs/HPCs (hematopoietic progenitor cells) for successful bone marrow transplantation. If successful, the proposed innovative approach has the potential to transform the field of bone marrow transplantation, and offers a curative option for patients with a wide spectrum of diseases including hematologic cancers, immune deficiency disorders, and aplastic anemia. The Specific Aims of our proposal are focused on achieving this objective. Aim 1. To determine if there is a synergistic effect between ICD-NOTCH and a hydrogel extracellular matrix in promoting definitive HSC/HPC expansion of human umbilical cord blood (hUCB). Aim 2. To compare if expansion approaches of hUCB that utilize ICD-NOTCH, SALL4, and a hydrogel extracellular matrix in combination will promote higher efficiency of short- term and long-term repopulation to marrow recovery.