干细胞的榜样：免疫细胞怎样自我更新

屈泰龙

当我们的器官衰老或损伤时，它们的更新通常取决于组织中的干细胞，因为绝大多数的分化细胞已经丧失了分裂和产生新细胞的能力。由来自于柏林的马克斯·德尔布吕克分子医学中心（MDC）的Michael Sieweke和马赛的CIML中心共同领导的德法研究团队现在已经发现了人类巨噬细胞——一类专门的免疫细胞，几乎可以无限的分裂和自我更新。正如研究人员在科学（Science）杂志中所展示的，巨噬细胞通过激活类似于在胚胎干细胞中发现的基因网络来实现这一点。在未来该研究结果可以给再生医学和治疗提供新的方向。

我们的身体不断发生着变化：新的细胞不断更换特定的细胞以保持皮肤，肠道，血液和其他组织或损伤后修复。由于分化细胞通常不再能分裂，更新几乎总是由组织中的干细胞来完成，其能够连续产生新的细胞。最近研究人员已经发现了一些例外情况：某些已分化的免疫细胞类型仍具有自我更新能力。

巨噬细胞，在免疫防御中发挥着重要作用，也可以控制组织的再生和重建。

几年前，一个以德国免疫学家和干细胞研究员Michael Sieweke为首的研究团队在法国的CIML中心的研究表明，在一定条件下当特异性地分化为免疫细胞时，巨噬细胞可以分裂而不会失去它们已获得的特性。研究人员表明在小鼠中，调节基因阅读的被称为转录因子的蛋白质，在这个过程中起着决定性的作用。通过在巨噬细胞中关闭两个名为MafB和c-Maf的转录因子的基因操作，会引起细胞开始一个看起来是自我更新的程序。它们甚至在培养时可以无限地被维持并扩增——这在分化细胞中通常是不可能的。

在新的研究中，Sieweke的来自于柏林的MDC和法国的CIML的研究小组现在已经能够表明，这也适用于那些从没有经过基因操作小鼠的各种巨噬细胞。在MafB和c-Maf的浓度同时自然降低或短时间内受到抑制时，这种情况会发生。

“现在，我们问自己，这是怎么发生的——换句话说，是什么机制和基因允许分化的巨噬细胞变得能够自我更新？”Sieweke说。为了找出原因，研究人员比较了巨噬细胞和具有类似无限自我更新能力的胚胎干细胞。科学家比较了两种类型细胞的基因调节元件的样式和活跃的基因种类。

“事实证明，巨噬细胞含有一组处于休眠状态的基因，其可以重新被唤醒从而恢复自我更新能力，”Sieweke说。在这种情况下，研究人员作出了一个惊人的发现：巨噬细胞的基因网络和增殖胚胎干细胞中的非常相似。“可以说，在分化的细胞中含有休眠状态的干细胞基因，”Sieweke解释说。

虽然这两种类型细胞的基因网络非常相似，然而它们却以不同的方式进行管理：它们是由不同的转录因子和每个类型细胞特有的基因调控元件来控制。“但是好消息是，发现巨噬细胞可使用自己特异性的调控因子来激活发现于干细胞的自我更新基因，”Sieweke说。

他认为，这些发现最终将在再生医学中非常有用。“如果分化的细胞可以直接扩增，就有可能直接替换患病组织而不用再绕弯使用胚胎干细胞或诱导多能干细胞，”Sieweke说。他还说，休眠的基因网络也许能在其它类型的细胞中激活——例如成熟的肝细胞，也有能力进行分裂。

巨噬细胞移植的研究表明，巨噬细胞的移植也许确实对于再生医学来说有用。 Sieweke的团队已经表明，在实验室的培养基中生长的巨噬细胞不会失去其性能。当注射到小鼠中，细胞成功地重新融合到组织并发挥它们全部的正常功能。这些细胞不仅能够抵抗感染，还在组织维持中发挥着重要的作用，并且也能满足再生需要。“它们可谓是组织的园丁或守护者，”Sieweke解释说。

屈泰龙

Role model stem cells: How immune cells can self-renew

When our organs age or wear out, their renewal usually depends on a few stem cells in the tissue, because the vast majority of differentiated cells have lost their ability to divide and generate new cells. A German-French team led by Michael Sieweke from the Max Delbrück Center for Molecular Medicine (MDC) in Berlin and the Centre d'Immunologie de Marseille-Luminy (CIML) in Marseille has now discovered how human macrophages, a type of specialized immune cell, can nevertheless divide and self-renew almost indefinitely. As the researchers show in the journal Science, the macrophages achieve this by activating a gene network similar to one found in embryonic stem cells. In the future the findings could provide new directions in regenerative medicine and therapies.

Our body is constantly changing: new cells continually replace specialized cells to maintain the skin, intestine, blood, and other tissues or repair them after an injury. Since differentiated cells are usually no longer able to divide, the renewal is almost always accomplished by stem cells specific to the tissue, which are capable of continually generating new cells. Recently researchers have discovered some exceptions: some types of immune cells which have already differentiated possess a capacity for self-renewal.
Macrophages, which play an important role in immune defenses, can also control tissue regeneration and renewal.
A few years ago, a team led by German immunologist and stem cell researcher Michael Sieweke at the French CIML showed that under certain conditions macrophages can divide without losing features they have acquired while specializing into immune cells. The researchers had shown in mice that proteins that regulate the reading of genes, called transcription factors, play a decisive role in this process. Genetic manipulations that turned off two transcription factors named MafB and c-Maf in the macrophages caused the cells to start what appeared to be a self-renewal program. They could even be maintained and expanded almost indefinitely in cell cultures - which is usually not possible with differentiated cells.
In the new study, Sieweke's research team from the MDC in Berlin and the CIML in France have now been able to show that this also works with various macrophages taken from mice that have not undergone genetic manipulations. This happened when concentrations of both MafB and c-Maf were naturally low or were inhibited for a short time.
"We now asked ourselves how this is possible - in other words, what mechanisms and genes allow the differentiated macrophages to switch on self-renewal?" Sieweke says. To find out the researchers compared the macrophages to embryonic stem cells, which have a similar, unlimited capacity for self-renewal. The scientists compared the patterns of gene regulatory elements and genes that were active in the two types of cells.
"As it turned out, the macrophages contain a set of dormant genes that can be reawakened and thus enable self-renewal," Sieweke says. In this context, the researchers made a surprising discovery: the macrophage genes work together in a network very similar to one that is switched on in proliferating embryonic stem cells. "You could say that the differentiated cells contain dormant stem cell genes," Sieweke explains.
While the gene networks in the two types of cells are very similar, they are managed in different ways: they are controlled by different transcription factors and gene regulatory elements which are specific to each type of cell. "But it is good news to discover that macrophages can activate the self-renewal genes found in stem cells using their own very specific regulatory factors ," Sieweke says.
He believes that these findings will ultimately be useful in regenerative medicine. "If differentiated cells could be expanded directly, it might be possible to replace diseased tissue without taking a detour via embryonic or induced pluripotent stem cells," Sieweke says. He adds that the dormant gene network may also be activated in other types of cells - mature liver cells, for example, have the ability to divide as well.
Transplantation studies with macrophages suggest that such transplantations of macrophages might indeed be useful for regeneration. Sieweke's teams have already shown that macrophages grown in laboratory cultures do not lose their properties. When injected into mice, the cells successfully re-integrate into tissues and perform all of their normal functions. The cells are not only able to fight infections, but also have an important function in maintaining tissues and are needed for regeneration. "They are, so to speak, the gardeners or guardians of the tissue," Sieweke explains.