From the Journals

Chemo-resistant reserve HSCs maintained in bone marrow



A small subpopulation of quiescent hematopoietic stem cells (HSCs) that restores the HSC pool and supports hematopoietic regeneration after chemotherapy has been identified, researchers reported.

Dr. Linheng Li of Stowers Institute for Medical Research

Dr. Linheng Li

These “reserve” HSCs were resistant to chemotherapy, whereas “primed” HSCs were sensitive to DNA damage from chemotherapy, the researchers said.

Both reserve and active stem cells were maintained in the bone marrow by specific niches, researchers demonstrated in experiments described in detail in Cell Reports.

Of note, primitive reserve HSCs were maintained in a bone marrow region that enriches N-cadherin expressing (N-cad+) bone and marrow stromal progenitor cells. According to investigators, those N-cad+ cells protected primitive reserve HSCs from chemotherapy-related stress, which survived to support hematopoietic regeneration after myeloablation.

These findings advance understanding of HSC biology, and could open new avenues for treating blood diseases and autoimmune disorders.

“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,” study senior author Linheng Li, PhD, a researcher at Stowers Institute for Medical Research in Kansas City, Mo., said in a statement.

Hematopoietic stem cells are heterogeneous, with some maintained in an active state, and others in a quiescent state that is related to their self-renewal capacity and linked to low metabolic activity, sometimes called HSC dormancy or hibernation, Dr. Li and his coinvestigators explained in their report.

However, despite their quiescence, the majority of those HSCs will not survive chemotherapeutic stress, they added.

A small subpopulation of cells termed reserve HSCs can survive stress related to 5-fluorouracil chemotherapy in mice and following transplantation, Dr. Li and his colleagues demonstrated in experiments described in the paper. By contrast, a much larger population of quiescent cells, primed HSCs, were chemotherapy sensitive.

“Most likely, primed HSCs reflect a transitional state between [reserve HSCs] and proliferating [short-term HSCs],” Dr. Li and his colleagues said in their report.

In one key experiment, Dr. Li and his coinvestigators used a cell surface marker to isolate reserve HSCs and primed HSCs, which were transplanted into mice. Following engraftment, the mice were treated with 5-fluorouracil. They found that reserve HSCs, reflected by their derived blood cells, were unaffected by treatment, whereas derivatives of primed HSCs declined.

In another experiment, the researchers labeled HSCs with fluorescent tags to identify their location in the bone marrow. They found reserve cells concentrated in a specific bone marrow niche adjacent to N-cad+ cells.

The N-cad+ cells were bone and marrow stromal progenitor cells (BMSPCs), giving rise to osteoblasts, adipocytes, and chondrocytes, according to investigators.

Ablating the N-cad+ niche cells impaired reserve HSC maintenance in both homeostasis and regeneration, investigators added.

The work was supported by the Stowers Institute for Medical Research, the National Cancer Institute, and other grant support. The researchers reported that they had no competing interests related to the study.

SOURCE: Zhao M et al. Cell Rep. 2019 Jan 15;26(3):652-69.e6.

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