Blood-Forming Stem Cells Have Back-Up System in Stressed Condition, New Study Shows

Blood-forming (hematopoietic) adult stem cells reside deep in the bone marrow and are responsible for regenerating the body’s blood supply including red blood cells, white blood cells, and platelets. In a study published this week in the journal Cell Reports, a team of researchers from China and the United States investigated how these cells, despite being sensitive to DNA damage, manage to repopulate blood cells after chemotherapy or injury. They found that a subset of hematopoietic adult stem cells called ‘reserve’ hematopoietic stem cells (HSCs) are resistant to chemotherapy. These reserve HSCs are located in a specialized niche, composed of cells on the inner bone surface expressing the molecule N-cadherin, in mouse bone marrow.

Zhao et al demonstrate that HSCs have a back-up system in stressed condition. Both reserve and active stem HSCs are maintained in the bone marrow by specific niches. While the latter are chemo-sensitive, the former survive and restore stem cells, and thereby generate the blood system. Image credit: Zhao et al, doi: 10.1016/j.celrep.2018.12.093.

Zhao et al demonstrate that HSCs have a back-up system in stressed condition. Both reserve and active stem HSCs are maintained in the bone marrow by specific niches. While the latter are chemo-sensitive, the former survive and restore stem cells, and thereby generate the blood system. Image credit: Zhao et al, doi: 10.1016/j.celrep.2018.12.093.

Every second, two million new blood cells are churned out by the amazing, regenerative HSCs that reside in the core of most bones.

Only a fraction of these cells actively move through the cell cycle at any given time; the rest lie in an inactive or quiescent state, which was once believed to protect them from harm.

However, several studies have shown that the majority of these quiescent HSCs are sensitive to DNA damage from chemotherapy.

Over a decade ago, Stowers Institute for Medical Research’s Dr. Linheng Li suggested that a special population of HSCs that are resistant to damage might still reside in the bone marrow, hidden in some unexplored niche.

“Under severe stress — radiation or chemotherapy that injures blood cells, including primed hematopoietic stem cells – that’s when reserve cells kick in,” he said.

In the new study, Dr. Li and colleagues undertook a series of experiments using a mouse model to prove that these cells exist.

A key experiment utilized a cell surface marker to isolate reserve and primed HSCs.

The researchers transplanted reserve HSCs or primed HSCs into recipient animals.

After the engraftments were established, they treated recipient mice with the chemotherapy agent 5-fluorouracil (5-FU).

While the primed HSCs reflected by their derived blood cells began to decline after treatment, the reserve HSCs’ derivatives were unscathed.

“In effect, we showed that hematopoietic stem cells have functionally distinct subpopulations — one that acts under normal conditions, and the other that acts under times of stress,” Dr. Li said.

Next, the scientists examined bone and marrow from transplanted mice, labeling the reserve cells with fluorescent tags and studying them microscopically to pinpoint their location in the bone marrow.

They spotted the fluorescently labeled cells lurking in a specialized niche along the inside surface of the bone, adjacent to a population of cells known as N-cadherin+ bone-lining cells.

They found that these N-cadherin+ bone-lining cells are mesenchymal or skeletal stem cells with the potential to produce bone, cartilage, and fat. Therefore, N-cadherin may be used as a marker to isolate skeletal stem cells and may have potential uses in bone and cartilage regenerative medicine.

These N-cadherin+ bone-lining cells appear to protect the reserve cells from injury by feeding them survival factors like the aptly named stem cell factor and others.

When the team depleted these support cells, the reserve cells were no longer able to survive chemotherapy treatment.

“Interestingly, we found that N-cadherin+ cells lining the bone are also resistant to chemotherapy, while stromal cells in the central marrow are sensitive to chemotherapy, which allows N-cadherin+ cells to better support the reserve stem cells,” said co-author Fang Tao, also from the Stowers Institute for Medical Research.

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Meng Zhao et al. N-Cadherin-Expressing Bone and Marrow Stromal Progenitor Cells Maintain Reserve Hematopoietic Stem Cells. Cell Reports 26 (3); doi: 10.1016/j.celrep.2018.12.093

 

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