细胞因子Midkine和Pleiotrophin对造血干细胞生物学作用的研究

Although self-renewal is the central property of stem cells, the underlying mechanism remains inadequately defined. Hematopoietic stem cell (HSC) is the prototype organ-regenerating stem cell, and by far the most studied type of stem cell in the body. HSCs play an essential role in the maintenance of multiple lineages of blood cells through their dual ability to self-renew and to differentiate into progenitors of various lineages. Successful expansion of HSCs would greatly benefit the treatment of disease and the understanding of crucial questions of stem cell biology. The midkine (MK) family consists of only two members, namely MK and pleiotrophin (PTN). MK and PTN share receptors and biophysical characteristics, such as a heparin-binding property. Previous studies have revealed the importance of these growth factors in the maintenance of embryonic stem cell and neural stem cells. Furthermore, it has been identified that PTN is a typical regulator of HSC expansion. Interestingly, we recently found that administration of MK to 5-FU treated or to irradiated mice caused a pronounced expansion of hematopoietic stem and progenitor cells in vivo, indicating that MK is also a regenerative growth factor for HSCs. However, little is known about the mechanisms of these two cytokines that regulate HSC expansion and regeneration. In this study, we'll seek to elucidate the mechanism underlying MK and PTN pathway's individual and combined contribution to HSC regulation utilizing knockout mouse models. We'll also attempt to establish a culture system using these growth factors and to develop an ex vivo expansion protocol for HSCs without functional impairment. Analysis of MK and PTN as growth factors for mouse HSCs in this study might be useful to understand the mechanism control in ex vivo expansion of human bone marrow or cord blood HSCs. Moreover, the observation may also be useful in the self-renewal of other stem cells as part of a transplantation or gene therapy protocol.

造血干细胞（HSC）具有高度的自我更新和多向分化的潜能。机体内的造血微环境通过产生分泌因子和基质蛋白等细胞外信号分子对HSC的稳态维持起了重要的生理作用。Midkine（MK）与Pleiotrophin（PTN）在蛋白构造上明显不同于其它的细胞因子，独立的构成了一个对干细胞活性起重要调节作用的生长因子家族。研究已表明，PTN可以明显促进HSC的自我复制及再生（Nat. Med.， 2010），然而PTN在微环境中对HSC的调控机制，及其家族成员MK对HSC生物学作用的信息,在国际上还处于研究空白阶段。本项目将首次以MK、PTN基因敲除小鼠模型为研究对象，通过HSC移植及体外培养等多方位的研究手段，对MK、PTN在HSC自我复制与分化过程中的生理功能及其分子调控机制进行系统的研究。预期本项目的研究成果不仅将明显提高我国在相关领域的国际科学地位，而且具有直接的临床指导价值和巨大的潜在社会效益。