遗传性免疫缺陷性疾病，如FHL、CHS、GS-2、XLP等，感染可引起致死性炎症反应。目前，异体造血干细胞移植（SCT）是治愈这些疾病的唯一方法。然而，造血干细胞供者的限制及急慢性移植物抗宿主病（GVHD）等因素使异体SCT存在一定的风险。如能应用自体替代异体SCT可以更大程度挽救遗传性免疫缺陷性疾病患者的生命，提高患者的生活质量。干细胞以及基因突变矫正技术的发展使得这一设想有望成为可能。本研究拟采用携带穿孔素（PRF1）或STX11纯合子点突变的FHL患者为研究对象，建立患者自体iPSC或MSC细胞系，利用同源重组相关技术矫正突变基因；继而诱导这些患者自体的iPSC或MSC分化为HSC；检测HSC分化红细胞（RBC）功能；G带染色体核型分析、微阵列比较基因组杂交技术（阵列-CGH）和全基因组测序（WGS）技术探讨由基因矫正后的iPSCs和MSCs分化来源的HSC的生物安全性。该研究项目的成功为进一步临床前和临床研究奠定一定的基础，为治疗和治愈遗传性免疫缺陷性疾病提供了新的方法，并为发展其他血液疾病（如再生障碍性贫血等血液系统恶性肿瘤）的自体SCT技术奠定一定的基础。

Inherited immune defects eg familial hemophagocytic lymphohistiocytosis (FHL), Chediak-Higashi symdrom (CHS), Griscelli syndrome 2 (GS-2), X-linked lymphoproliferative syndrome (XLP) are fatal when hyperinflammation triggered by infections occurs. To date, allogenetic hematopoietic stem cell transplantation (allo-HSCT) is the only known cure for these disorders. Unfortunately many patients die before a donor is available due to limited HLA-matched donors. Moreover, about 20%-40% patients die from allo-SCT mediated acute and chronic graft versus host disease (GVHD). In addition, the drugs used for management of GVHD are relatively toxic for liver and kidney, which significantly affects the life quality of patients who have undergone allo-SCT. In contrast, autologous SCT do not have these disadvantages and is therefore an attractive approach to treat these patients. Inducible pluripotent stem cells (iPSC) and mesenchymal stem cells (MSC) hold great promise for developing such stem cell treatment approach by using mutation correction technology to remove disease gene mutations in the autologous iPSC or MSC. Theoretically, through in vitro induction of the gene corrected iPSC or MSC differentiation into hematopoietic stem cell (HSC) and expansion of HSC in a large scale, the allo-SCT could then be replaced by autologous SCT..We aim to establish autologous iPSC or MSC cell lines from FHL patients who carries one homozygous gene mutation in the PRF1 (perforin) gene, and to correct the disease gene mutation using homologous recombination and zinc-finger nucleases technology; to induce the gene corrected iPSC or MSC differentiation into HSC by cell culture and molecular genetic techniques; to generate NK cells from HSC derived from FHL iPSC or MSC and test the perforin expression and cytotoxicity; to evaluate of the biological function of the HSC derived from FHL iPSC or MSC in vitro and vivo by cell culture, flow cytometry and other related techniques; determine biosafety of the autologous HSC derived from FHL iPSC or MSC by G-band chromosome karyotyping, array-CGH and whole genome sequencing technology. The success of the proposed study will pave a novel avenue to treat and cure inherited immune defects and provide valuable basis for developing auto-SCT system for other hematological diseases such as aplastic anemia and some of hematological malignancies.

山东大学与卡罗林斯卡医学院干细胞合作实验室主要研究工作着眼于端粒、MSC与疾病发生发展的关系，重点研究在癌症进程中变化规律与作用方式，寻找肿瘤发病机制以及的潜在干预靶点，寻找新的治疗策略。研究发现硼替佐米介导的端粒酶下调和端粒稳态破坏有助于恶性细胞的凋亡，硼替佐米诱导的hTERT表达和端粒功能障碍的下调都有助于其对癌细胞杀伤作用，hTERT可以赋予恶性细胞对基于硼替佐米的靶向癌症治疗的抗性，这可能具有重要的临床意义；间充质干细胞与NK细胞在多发性骨髓瘤发病中的作用机制及治疗作用，骨髓间充质干细胞的骨髓瘤相关性延长可能是IL- 6和MIP-1α在MM的BMMSCs中的表达，其中肿瘤微环境中的MSC可以促进MM和/或MM骨发育；汉族人群TERT rs2736100 AC基因型与上尿路上皮癌风险降低之间的关系，rs2736100 AC变体预测发生UTUC的风险降低；脐带间充质干细胞的输注缓解了强直性脊柱炎的症状，静脉输注uMSCs是安全，耐受性好的患者，有效缓解了疾病活动和临床症状。