肺是重要的造血器官-可以解释运动对慢性疾病的神奇治疗效果 Surprising New Role for the Lungs: Making Blood

肺是重要的造血器官-可以解释运动对慢性疾病的神奇治疗效果

Surprising new role for lungs: Making blood

Cells in mouse lungs produce most blood platelets and can replenish blood-making cells in bone marrow, study shows

加州大学旧金山分校2017年3月的这个伟大发现解释了为什么运动对慢性疾病有神奇的治愈效果。

一直以来，骨髓被认为是唯一的造血器官，但加州大学旧金山分校2017年3月发布了一个令人振奋的发现-原来肺也是一个重要的造血器官，不但可以制造血小板，还可以制造红血球和免疫细胞。

运用双光子内部成像技术，把绿色荧光蛋白(GFP)注入小鼠体内，研究人员发现，肺在哺乳动物体内扮演的角色比我们想象的要复杂得多，有新的证据表明，它们不仅有助于呼吸，而且在血液生产中也起着关键作用。

在小鼠实验中，研究小组发现，它们每小时产生超过1000万个血小板(微小的血细胞)，相当于动物血液循环中大部分的血小板。这与几十年来的假设相违背，即骨髓产生了我们所有的血液成分。

虽然人们知道肺会产生有限数量的血小板——称为巨核细胞的血小板形成细胞已经在肺中被识别出来——科学家们长期以来一直认为，负责血液生产的大部分细胞都保存在骨髓中。

研究人员还发现了一种以前不为人知的血液干细胞池，大量的以前隐藏的血液干细胞和巨核细胞祖母细胞(产生巨核细胞和红细胞的细胞)位于肺血管外——大约每只小鼠肺有100万。以前认为这些细胞被错误地认为主要存在于骨髓中。

巨核细胞和血液干细胞在肺中的发现引发了关于这些细胞如何在肺和骨髓之间来回移动的问题。为了解决这些问题，研究人员进行了一组巧妙的肺移植研究:

首先，将正常供体小鼠的肺移植到具有荧光巨核细胞的受体小鼠体内，并发现受体小鼠的荧光巨核细胞很快就出现在肺血管中。这表明，肺中产生血小板的巨核细胞起源于骨髓。

“巨核细胞从骨髓到肺都能产生血小板，这很有趣，”Guadalupe Ortiz-Munoz博士说，他也是Looney实验室的博士后研究员，也是该论文的另一位共同作者。“由于血液的机械力，或者可能是因为一些我们还不知道的分子信号，肺可能是血小板产生的理想生物反应器。”

在另一项实验中，研究人员将荧光巨核细胞祖细胞移植到具有低血小板计数的突变小鼠体内。这种移植产生了大量的荧光血小板，能迅速恢复正常水平，这种效应持续了几个月的观察时间——比单个巨核细胞或血小板的寿命长得多。对研究人员来说，这表明移植肺部的巨核细胞祖细胞已被受体小鼠的低血小板计数激活，并产生了健康的新的巨核细胞，以恢复正常的血小板生成。

最后，研究人员把被荧光标记的健康的肺组织植入其骨髓中缺少正常造血干细胞的突变小鼠体内。受体小鼠的骨髓的分析表明, 起源于移植肺的荧光细胞很快前往受损的骨髓，不仅生产血小板, 而且生产各种各样的血液细胞,包括中性粒细胞等免疫细胞,B细胞和T细胞。这些实验表明，肺可以容纳大量的红细胞祖细胞和干细胞，这些细胞和干细胞能够重建受损的骨髓，并恢复许多血液成分的产生。

这些实验表明，肺可以容纳大量的红细胞祖细胞和干细胞，这些细胞和干细胞能够重建受损的骨髓，并恢复许多血液成分的产生。

Using video microscopy in the living mouse lung, UC San Francisco scientists have revealed that the lungs play a previously unrecognized role in blood production. As reported online March 22, 2017 in Nature, the researchers found that the lungs produced more than half of the platelets -- blood components required for the clotting that stanches bleeding -- in the mouse circulation. In another surprise finding, the scientists also identified a previously unknown pool of blood stem cells capable of restoring blood production when the stem cells of the bone marrow, previously thought to be the principal site of blood production, are depleted.

"This finding definitely suggests a more sophisticated view of the lungs -- that they're not just for respiration but also a key partner in formation of crucial aspects of the blood," said pulmonologist Mark R. Looney, MD, a professor of medicine and of laboratory medicine at UCSF and the new paper's senior author. "What we've observed here in mice strongly suggests the lung may play a key role in blood formation in humans as well."

The findings could have major implications for understanding human diseases in which patients suffer from low platelet counts, or thrombocytopenia, which afflicts millions of people and increases the risk of dangerous uncontrolled bleeding. The findings also raise questions about how blood stem cells residing in the lungs may affect the recipients of lung transplants.

Mouse lungs produce more than 10 million platelets per hour, live imaging studies show

The new study was made possible by a refinement of a technique known as two-photon intravital imaging recently developed by Looney and co-author Matthew F. Krummel, PhD, a UCSF professor of pathology. This imaging approach allowed the researchers to perform the extremely delicate task of visualizing the behavior of individual cells within the tiny blood vessels of a living mouse lung.

Looney and his team were using this technique to examine interactions between the immune system and circulating platelets in the lungs, using a mouse strain engineered so that platelets emit bright green fluorescence, when they noticed a surprisingly large population of platelet-producing cells called megakaryocytes in the lung vasculature. Though megakaryocytes had been observed in the lung before, they were generally thought to live and produce platelets primarily in the bone marrow.

"When we discovered this massive population of megakaryocytes that appeared to be living in the lung, we realized we had to follow this up," said Emma Lefrançais, PhD, a postdoctoral researcher in Looney's lab and co-first author on the new paper.

More detailed imaging sessions soon revealed megakaryocytes in the act of producing more than 10 million platelets per hour within the lung vasculature, suggesting that more than half of a mouse's total platelet production occurs in the lung, not the bone marrow, as researchers had long presumed. Video microscopy experiments also revealed a wide variety of previously overlooked megakaryocyte progenitor cells and blood stem cells sitting quietly outside the lung vasculature -- estimated at 1 million per mouse lung.

Newly discovered blood stem cells in the lung can restore damaged bone marrow

The discovery of megakaryocytes and blood stem cells in the lung raised questions about how these cells move back and forth between the lung and bone marrow. To address these questions, the researchers conducted a clever set of lung transplant studies:

First, the team transplanted lungs from normal donor mice into recipient mice with fluorescent megakaryocytes, and found that fluorescent megakaryocytes from the recipient mice soon began turning up in the lung vasculature. This suggested that the platelet-producing megakaryocytes in the lung originate in the bone marrow.

"It's fascinating that megakaryocytes travel all the way from the bone marrow to the lungs to produce platelets," said Guadalupe Ortiz-Muñoz, PhD, also a postdoctoral researcher in the Looney lab and the paper's other co-first author. "It's possible that the lung is an ideal bioreactor for platelet production because of the mechanical force of the blood, or perhaps because of some molecular signaling we don't yet know about."

In another experiment, the researchers transplanted lungs with fluorescent megakaryocyte progenitor cells into mutant mice with low platelet counts. The transplants produced a large burst of fluorescent platelets that quickly restored normal levels, an effect that persisted over several months of observation -- much longer than the lifespan of individual megakaryocytes or platelets. To the researchers, this indicated that resident megakaryocyte progenitor cells in the transplanted lungs had become activated by the recipient mouse's low platelet counts and had produced healthy new megakaryocyte cells to restore proper platelet production.

Finally, the researchers transplanted healthy lungs in which all cells were fluorescently tagged into mutant mice whose bone marrow lacked normal blood stem cells. Analysis of the bone marrow of recipient mice showed that fluorescent cells originating from the transplanted lungs soon traveled to the damaged bone marrow and contributed to the production not just of platelets, but of a wide variety of blood cells, including immune cells such as neutrophils, B cells and T cells. These experiments suggest that the lungs play host to a wide variety of blood progenitor cells and stem cells capable of restocking damaged bone marrow and restoring production of many components of the blood.

"To our knowledge this is the first description of blood progenitors resident in the lung, and it raises a lot of questions with clinical relevance for the millions of people who suffer from thrombocytopenia," said Looney, who is also an attending physician on UCSF's pulmonary consult service and intensive care units.

In particular, the study suggests that researchers who have proposed treating platelet diseases with platelets produced from engineered megakaryocytes should look to the lungs as a resource for platelet production, Looney said. The study also presents new avenues of research for stem cell biologists to explore how the bone marrow and lung collaborate to produce a healthy blood system through the mutual exchange of stem cells.

"These observations alter existing paradigms regarding blood cell formation, lung biology and disease, and transplantation," said pulmonologist Guy A. Zimmerman, MD, who is associate chair of the Department of Internal Medicine at the University of Utah School of Medicine and was an independent reviewer of the new study for Nature. "The findings have direct clinical relevance and provide a rich group of questions for future studies of platelet genesis and megakaryocyte function in lung inflammation and other inflammatory conditions, bleeding and thrombotic disorders, and transplantation."

The observation that blood stem cells and progenitors seem to travel back and forth freely between the lung and bone marrow lends support to a growing sense among researchers that stem cells may be much more active than previously appreciated, Looney said. "We're seeing more and more that the stem cells that produce the blood don't just live in one place but travel around through the blood stream. Perhaps 'studying abroad' in different organs is a normal part of stem cell education."