造血干细胞起源于胎盘，接受胎盘的营养

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Blood Stem Cells Originate And Are Nurtured In The Placenta

ScienceDaily (Mar. 6, 2008) — Solving a long-standing biological mystery, UCLA stem cell researchers have discovered that blood stem cells, the cells that later differentiate into all the cells in the blood supply, originate and are nurtured in the placenta.

The discovery may allow researchers to mimic the specific embryonic microenvironment necessary for development of blood stem cells in cell culture and grow them for use in treating diseases like leukemia and aplastic anemia, said Dr. Hanna Mikkola, a researcher in the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and senior author of the study.

“It was a big mystery, where these cells originated,” said Mikkola, an assistant professor of molecular, cell and developmental biology. “This is the first time we can really say definitively that blood stem cells are generated in the placenta. There’s no more speculation.”

The study is published March 6, 2008 in the journal Cell Stem Cell. Researchers in Mikkola’s lab are working now to replicate this work, done in mouse models, in humans.

“If we want to fully harness the potential of embryonic stem cells to treat disease, it’s critical for us to learn how to make tissue specific stem cells,” said Mikkola, who also is a researcher at UCLA’s Jonsson Comprehensive Cancer Center. “We can learn that by studying what happens during embryonic development.”

Scientists now can take embryonic stem cells, the cells that can become any tissue type in the body, and coax them into becoming all the cells in the blood supply, such as red and white blood cells and platelets. However, they can’t make blood stem cells that self-new, or make more of themselves, and don’t differentiate prematurely when transplanted into patients.

The only way this currently can be achieved is by manipulating the cell’s nuclear regulatory machinery with genes using retroviruses. To generate blood stem cells that are safe for use in patients, it is imperative that scientists learn how to generate self-renewing blood stem cells in a more natural way, by providing the correct developmental cues from the environment in which the cells develop.

Currently, patients with certain types of leukemia have one shot at a cure – a bone marrow transplant. However, there aren’t nearly enough bone marrow donors to provide patients with perfect matches. Use of a less than perfect donor match carries a risk of graft vs. host disease, in which the immune cells from the donated marrow attack the body of the transplant patient. Cord blood contains blood stem cells, but not in large enough quantities to transplant an adult patient, Mikkola said.

If researchers could grow blood stem cells, those cells could be transplanted into these patients. The blood stem cells would then differentiate into a new, and healthy, blood supply. And with the recent success in creating induced pluripotent stem cells (iPS) from human skin cells, a patient’s own skin cells could perhaps be used to create iPS cells. Those cells could then be transformed into blood stem cells, creating an immune-compatible source of blood supply that eliminates the risk of graft vs. host disease.

In her previous research, Mikkola and collaborators in Harvard and France had discovered that the placenta contained a large pool of blood stem cells, but it wasn’t clear if they originated elsewhere and migrated to the placenta to self-renew. Using a unique mouse model, a mouse embryo without a heartbeat, Mikkola and her team were able to find the blood stem cells at the site of their origin because there was no circulation of blood through the body.

“Using this model, we identified that the placenta has the potential to make hematopoietic (blood) stem cells with full differentiation ability to create all the major lineages of blood cells,” Mikkola said. “The placenta acts as a sort of kindergarten for these newly made blood stem cells, giving them the first education they need.”

It was previously known that blood stem cells could be found in the dorsal aorta, but there were so few located there that scientists reasoned it could not be the sole source of blood stem cells in the embryo. Mikkola’s discovery indicates that the blood stem cells are generated in the large arteries of the embryo and placenta, and then move to a specific site, or niche, where they expand and mature.

This recent study indicates that the first niche for expansion of blood stem cells is the placenta’s vascular labyrinth, where oxygen and nutrients are exchanged between the mother and the fetus. The findings show the placenta harbors two different microenvironments, one area where blood stem cells originate and another area, the labyrinth, that nurtures them, allowing them to expand in number.

These niches serve different roles and could provide clues to researchers seeking to grow blood stem cells. Mikkola now is seeking to uncover the critical biological signals and cues during embryonic development that drive blood stem cell generation and expansion and keep the cells from differentiating prematurely.

“The labyrinth is a source of many growth factors and cytokines,” Mikkola said. “We just need to identify what those signaling molecules and cues are that are nurturing those cells when in the placenta.”

Mikkola is confident the study can be confirmed in humans. “Everything we’re learning suggests we will find the same thing in the human placenta,” she said.
造血干细胞起源于胎盘，接受胎盘的营养科技日报（2008年3月6号）---UCLA干细胞研究者们解决了一个长期存在的生物学谜团，他们发现造血干细胞起源于胎盘，接受胎盘的营养。这项发现也许可以使研究者们模拟特殊的胚胎微环境，这种微环境是培养和扩增造血干细胞以用来治疗像白血病和再生障碍性贫血一类疾病所必须的，Hanna Mikkola说。Eli and Edythe再生医学和干细胞研究中心，该研究的高级作者。 “这类干细胞的起源是个很大的谜团，”Mikkola说，分子、细胞和发育生物学助理教授。“这是第一次我们敢肯定的说造血干细胞起源于胎盘。没有更多需要解释的。”该研究发表与Cell Stem Cell杂志2008-3-6。Mikkola’s 实验室的研究者们现在正在在老鼠模型和人体重复这项工作。“如果我们要充分发掘潜力的胚胎干细胞用于治疗疾病，关键是我们要学习如何获得组织特异性干细胞，”Mikkola说，他同时是UCLA Jonsson综合癌症中心研究员。“我们可以通过研究胚胎的发育来学习。”科学家们现在可以获得胚胎干细胞，这类细胞可以分化为全身各种类型的组织，可以被诱导分化为用于血液供应的各类血细胞，比如红细胞、白细胞和血小板。然而，它们不能使血液中的干细胞自我更新，自我扩增，亦不能移植到患者体内时过早的分化。目前能实现这的唯一办法是通过逆转录病毒在基因水平处理细胞内核调节机制。为了制造出能安全应用与人体的造血干细胞，科学家们必须研究一种更自然的方法来制造出能够自我更新的造血干细胞，该方法为细胞发育提供正确的生长环境。目前，一些特定类型的白血病患者有一种可治愈的办法----骨髓移植。然而，没有足够的骨髓供者为患者提供完全匹配的骨髓。 使用不完全匹配的骨髓存在发生GVHD（移植物抗宿主病）的风险，即来自供者骨髓的免疫细胞攻击受者。脐血含有造血干细胞，但数量不足以用来移植于成人，Mikkola说。如果研究者可以培养造血干细胞，而细胞可以用来移植给患者。那么造血干细胞可以分化为新的、健康的血液供给。最近成功创造出由人体皮肤诱导的多能干细胞（iPS）----患者本身的皮肤也许可以用来制造iPS细胞。这些细胞进而可以转变为造血干细胞，创造出免疫适合的血液供给，排除GVHD发生的风险。在她的前期研究中，Mikkola和其同事在哈佛和法国发现胎盘中存在巨大的造血干细胞池，但是若它们起源于其他任何地方并迁徙到胎盘自我更新，那它们是不干净的。Mikkola和她的研究小组使用一独特的小鼠模型，小鼠胚胎无心跳，这样能够找到造血干细胞的起源位置，因为没有血液循环。 “使用该模型，我们发现胎盘有制造造血干细胞的潜力，该细胞具有全分化能力，可以制造出血细胞的主要谱系，”Mikkola说。“对于这些新制造的造血干细胞，胎盘就像一幼儿园给它们必要的教育。”曾经我们知道造血干细胞可以在背主动脉发现，但该部位细胞数非常少，所以科学家们推理该部位不是胚胎的造血干细胞的唯一起源。Mikkola的发现表明造血干细胞产生于胚胎的大动脉和胎盘，然后迁徙到特定部位或适当的地方，在那里扩增和成熟。这项最近的研究显示，造血干细胞扩散的第一个适宜位置是胎盘的血管迷路，那里有母亲和胎儿间的氧气和养分交换。调查结果显示胎盘存在两种不同的微环境，一个地方是造血干细胞起源，另一个地方----迷宫，培育他们，让他们来扩大数量。这些适宜的地方充当不同的角色，可以为研究者寻找培养造血干细胞提供线索。Mikkola目前正在正设法找出胚胎发育过程中推动血液干细胞的生成和扩增并维持细胞不分化过早的那些关键的生物信号和线索。 “迷路是很多生长因子和细胞因子的起源，”Mikkola说。“我们只需要寻找出在胎盘中营养这些细胞的那些信号分子和线索。”Mikkola有自信该研究能在人体得到证实。“我们所学的每件事都支持我们将在人体胎盘发现同样的结果，”她说。