“Hematopoietic stem cells walk on a narrow balance between leukemia and aging”

Marieke von Lindern

Marieke von Lindern PhD

Marieke von Lindern is head of the department of Hematopoiesis. Her department investigates the process by which mature peripheral blood cells are formed from the hematopoietic stem cell (HSC). Important topics are aging of stem cells and the culture and maturation of various blood cell types from progenitor cells, isolated from peripheral blood.

In 2012 the Dutch Hendrikje van Andel died at the age of 115, at the time the oldest person in the world. Recently, researchers reported that at the end of her life all of her peripheral blood cells were derived from only two active HSCs. How did that come about?
“Hendrikje van Andel started life with about 1300 active HSC. During her life, her HSCs have renewed and differentiated into various lineages of the blood cell system. Almost all of Mrs van Andels HSCs were burned out at the end of her life. All those numerous replications may have caused mutations in the DNA of the stem cells. This could have led to unlimited growth, leukemia, if it weren’t for her tumor suppressor genes that regulate proliferation and differentiation. They make cells that have gained tumor characteristics to go into apoptosis or differentiation to mature cells that lack replication potential. In fact, aging protects us from having cancer. Stem cells walk on a narrow balance between the unlimited growth seen with leukemia on the one hand aging on the other hand I think Mrs van Andels stem cells have done an extremely good job in finding that balance.”

Aging is a natural occurring process. When does aging of HSCs become a problem?
“Some examples of extreme aging are found in syndromes or diseases like progeria. But what is more relevant for my department is the Myelodysplastic syndrome (MDS). Patients with MDS may develop severe anemia and frequently require blood transfusions. In some cases, the disease worsens and the patient develops low blood counts, caused by progressive bone marrow failure. There is still not much known about the syndrome and various theories about its nature exist. In some cases MDS may be caused by exposure to certain chemicals such as those in solvents that were used for paint . What we do know is that in those patients the tumor suppressor genes are upregulated, resulting in a strong pressure towards aging. If cells manage to escape from that pressure, the MDS patient may develop leukemia. As those leukemic cells have already escaped natural tumor suppression, it is particularly difficult to find effective treatment for those patients.”

Dream or reality: an injection with young blood for all elderly people?
“I think the recent reports about rejuvenating old mice by giving them young blood are highly important for aging research. To me however, prevention of aging is not a goal in itself. For some diseases that we study, however, aging may be an underlying cause. With our research on aging of HSCs we primarily aim at elderly with bone marrow failure, chronic leukemia and MDS, who are currently treated with cord blood stem cells. Therefore we work closely together with the Laboratory for Cell Therapy and the Cord blood bank here at Sanquin.”

You have received a prestigious grant for culturing red blood cells from stem cells. How does that go about?
“We start with the buffy coat, the fraction of white cells in the blood donation bag, which is usually disposed of. From this fraction we culture red cell progenitors under defined conditions. We let them first expand to a very large number of cells, and subsequently we differentiate these cells into reticulocytes. When administered to a patient the reticulocytes will further mature into erythrocytes. In theory, we are currently able to double the number of red blood cells from one donation. I think that in 1.5 to 2 years we will be ready to do the first mini blood transfusions in volunteers in order to test our culture system for safety and immunogenicity. At the same time we want to develop a more cost-effective and efficient way to culture blood cells by making stable red blood cell lines. To do so we are generating induced pluripotent stem cells (iPSs) out of blood cells, which we dedifferentiate by introducing four different transcription factors. In fact, iPSs are very similar to embryonic stem cells, but go without ethical controversies. From iPSs, which are an immortal source, we can generate any amount of red blood cell by adding a cocktail of growth factors. In addition, we’d like to study the generation and culture of erythroblasts as an alternative source for producing red blood cells.”

What kind of patients may receive cultured blood in the future?
“The reason that we want to culture blood is that for some patients it is very hard to find matching donor blood. That particularly holds for patients that frequently need blood transfusions. We regularly see patients making antibodies to donor blood, even if there is only a small difference in minor blood groups. That goes for patients with chronic anemia, MDS, but most of all for patients with sickle cell disease. Sickle cell patient are usually from African origin, their blood groups differ from the greater part of our blood bank population. The number of suitable donors for sickle cell patients is therefore limited and their blood is needed frequently. There is a great demand for matching blood for these patients. Generating red blood cells from iPSs of those rare donors could meet that demand. In addition, we could even make functional red blood cells from the sickle cell patient’s own iPSs. It appears that erythrocytes cultured from iPSs primarily express the fetal gamma globin rather than beta globin, the adult hemoglobin, which is affected in sickle cell disease. I hope that in the future we will be able to culture a bag of matching blood for each patient whenever needed.”

Getting back to Hendrikje van Andel: what is aging to you?
“To me, healthy aging is more important than aging itself. I try to enjoy life and do what is important to me now and not later in life. I am trying to live my life meaningfully. Thirty years ago we couldn’t have imagined where we are now in the field of science or society itself. I find it very difficult to think about my life thirty years from now.”

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