From stem cells to macrophages or Decision making in blood cells

The work of the team of Michael Sieweke is at the interface of immunology and the study of stem cells, cells that can renew themselves and differentiate into many cell types. There are large hopes that stem cells may revolutionize future medicine. These hopes are based on the idea that these immature ‘undecided’ cells can be coaxed into making large numbers of any particular cell type of the body to serve a therapeutic purpose.

Working on hematopoietic stem cells, the precursors of all our blood cells, the team discovered that the decision of these cells to develop into a particular blood cell type rather than another is not random but under the influence of external factors and internal receptiveness. Their findings may offer new possibilities to influence the choice of hematopoietic, and possibly other stem cells.

Recently the team also put into question the paradigm that once a cell becomes specialized, it loses its ability to proliferate. With a small genetic change, however, they managed to grow functional adult cells for extended periods. Regenerative medicine may well take the next step by expanding mature cells directly without going through stem cell intermediates!


Courtesy of Nature Reviews Immunology.

It is easy to see that our body is composed of different cell types. Clearly, our skin cells are different from those of the eye, and even if hidden from view, one suspects still different from the cells of our liver or brain. Yet in the beginning, all started with a single cell, the mother of all cells in the body! Up to the very early stages of embryonic development, cells can be isolated that can still give rise to any cell type of the body and form a complete organism. Veryimportant for research and applications, these pluripotent stem cells can also be grown virtually indefinitely in culture

As the body develops and cells mature, they lose these useful abilities. Yet, even in adults stem cells can still be found. They are already a bit more specialized, however, and produce only the set of cells that contribute to the composition of a single tissue and / or organs: liver, skin, brain, blood... Such multipotent stem cells also cannot be amplified in culture but have already resulted in important clinical applications, for example for blood stem cells.

Any use of stem cells will required to direct their development to desired mature cells. What are the signals then that trigger the differentiation of stem cells into one of many possible directions? To answer this old question in biology, Michael Sieweke has been studying the differentiation of hematopoietic stem cells, the ancestors of all our blood cells.

Go, become a white blood cell!

 Even in the adult organism the immune system retains the ability to continuously produce new immune cells, which enables it to flexibly respond to permanently changing environmental challenges, such as infection or injury. Thus, all the specialized blood cells are replaced continuously from hematopoietic stem cells, a small group of common precursors nestled in the bone marrow. Studying these cells in cell culture and in mice, Michael Sieweke has chosen this model to try to unlock the secrets of differentiation.

 The team of Michael Sieweke could show that differentiation of stem cells is not random but depends on both cell external and internal signals. The team demonstrated that inactivation of MafB, a cell intrinsic factor governing gene expression combined with a signal from the environment (a cytokine known as M-CSF) triggered the differentiation of hematopoietic stem cells into the myeloid lineage of the immune system (giving rise to granulocytes and monocytes, a subset of white blood cells with particular abilities to fight microbes).

The finding became possible, because Michael Sieweke was able to observe the birth of the first daughter cell of the linage: "With a label specifically identifying the myeloid cells, we observed at the scale of a single cell, the exact moment when the latter change their destiny..."

This fundamental discovery could solve one of the challenges of regenerative medicine: the mastery of controlled differentiation of stem cells. It could also shed new light on leukemia, where abnormal stem cells "forget" to engage in a process of differentiation, proliferate indefinitely in this usually transitional "mother" cell state and escape treatment.

Cell amplification without stem cells?

To obtain large numbers of desired therapeutic cells, must regenerative medicine go through the route of stem cells? Until recently the answer was yes, but again, a discovery of the team may change this.

Once a specialization is acquired, cells lose their ability to proliferate, simply because the body does not need an infinite number of specialized cells. Thus, the capacity for self renewal and functional specialization have long been regarded as incompatible, "A differentiated cell that proliferates is always seen as a potential problem since it is usually synonymous with cancer," says Michael Sieweke. "Yet we have challenged this doctrine: we have shown that it is possible for a cell to divide long-term in a differentiated state, with no signs of cancerous transformation, or loss of functions associated with its specialization."

To achieve this, the team genetically engineered mouse macrophages, differentiated cells of the myeloid lineage. By simultaneously inactivating two factors (c-Maf and MafB) that control cell proliferation in mouse macrophages, they restored their ability to divide indefinitely in culture without compromising features that make them macrophages.
More surprisingly, after a long expansion in culture, MafB and c-Maf deficient macrophages can be transplanted in mice, where they no longer proliferate and do not form tumors. Better yet, they integrate into their host tissues in a well-behaved manner and contribute to the protection of animals against bacterial infections, demonstrating that they have retained their functions in a whole organism.

MafB and c-maf deficient macrophages are specialized mature cells retaining the ability to ingest microbes but they acquired the amazing property to divide indefinitely in culture: cells are engulfing fluorescent beads (red circles) while continuously dividing in culture (green arrows). Copyright M Sieweke, CIML.

"It's a small revolution!" enthuses Michael Sieweke, "Imagine that in the near future, we could identify the factors equivalent to MafB and c-Maf not in macrophages, but in cells dedicated to the control of other cells the body. These factors could then be inactivated in a small sample of cells, multiplied in culture and then injected directly into the defective organ of a patient to repair it. No need for organ transplantation or stem cells! Obviously much remains to be done to make this dream come true. First we will still have to show that this approach works in humans and for other cell types."