Boning up on HSCs

The scarcity of hematopoietic stem cells (HSCs) severely limits bone marrow transplantation, which can cure many blood disorders and solid tumors. The Mount Sinai team reports that manipulation of metabolic activity around lysosomes can increase the potency of blood-forming stem cells in bone marrow transplantation by more than 90-fold.

“Hematopoietic stem cells lose their stem cell potential once they’re cultured in a dish, which limits their ability to be easily propagated in the laboratory. In order for these stem cells to maintain optimal potency, they shouldn’t be constantly dividing—putting them under metabolic stress that can alter their health and longevity. Instead, they should be in a dormant, or quiescent, state. But maintaining quiescence of blood stem cells outside of the body has been challenging,” noted Dr. Saghi Ghaffari, a professor of cell, developmental and regenerative biology in the Black Family Stem Cell Institute and The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, and lead investigator of the study.

“We discovered that lysosomes are key to the dormancy of these cells. We further learned that repressing lysosomal activity—rather than their stimulation—enhances stem cell quiescence and potency, and may have therapeutic value.”

Through their extensive in-vivo work in mice, the Mount Sinai scientists used an effective and specific lysosomal inhibitor that reduces lysosomal acidity and amino acid release in the cells. The net effect is to restore stem cells with activated lysosomes to a quiescent state. The study further found that the inhibition of glycolysis also enhances quiescence and potency of hematopoietic stem cells, which are believed to rely on glycolysis for their energy.

Scientists have been trying for years to generate more HSCs in the laboratory for clinical use.

“Our methodology is different from others in that it is based on quality rather than quantity. By restraining lysosomal activity, we produce fewer blood-forming stem cells for bone marrow transplantation, but they work much better because we’ve preserved and enhanced their potency,” explained Ghaffari, who is a recognized expert in blood disorders.

This work could be used to generate blood stem cells from cultured pluripotent stem cells, or to enhance the function of human blood stem cells for bone marrow transplantation—something that is being attempted in Ghaffari’s lab. It’s also led to many new questions regarding the contribution of lysosomes to stem cell quiescence and potency, and their potential therapeutic applications. Another impact of her lab’s work could be identifying and targeting stem cells that propagate blood malignancies, including leukemia.

In other HSC-related news involving Mount Sinai, a clinical-stage company known as Tacitus Therapeutics recently announced its launch in collaboration with Mount Sinai to develop stem cell therapies. The companies initially plan to target blood cancers and related clotting disorders.

“Promising discoveries by Mount Sinai scientific thought leaders may lead to new, essential cell-based therapies that will broadly benefit patients,” said Erik Lium, executive vice president and chief commercial innovation officer of Mount Sinai Innovation Partners. “We’re pleased to be collaborating with Tacitus to launch the next stage of development for these technologies.”

The collaboration’s first program, HSC100, is an investigational therapy based on allogeneic HSCs expanded from umbilical cord blood. It’s being investigated currently in an open-label Phase 1 clinical trial in the U.S. for treatment of hematological malignancies. The proprietary technology includes the use of an epigenetic modifier, valproic acid, to expand the number and the quality of HSCs found in cord blood collections.

Tacitus is building upon technology developed by and exclusively licensed from from Mount Sinai. The technology is based on research by scientific co-founders Drs. Ronald Hoffman and Camelia Iancu-Rubin, and it includes proprietary cell expansion, differentiation and engineering methods. Together, these methods manufacture healthy cells that overcome the limitations of traditional allogeneic cell transplantations.

HSCs can be collected from bone marrow, circulating blood or umbilical cord blood (CB) of healthy donors. In this process, doctors infuse healthy HSCs into the patient’s bloodstream, where they migrate to the bone marrow to grow or engraft. HSC transplants are common but significant barriers to success exist, including high levels of graft-versus-host disease, low numbers of healthy cells obtained from CB, and increased risk of bleeding due to delayed megakaryocyte engraftment.

Development of this technology was enabled by the New York State Stem Cell Science program, NYSTEM. As a New York State Department of Health initiative, NYSTEM awarded a $1-million grant to Hoffman in 2010 that supported the original research underpinning this platform technology. In 2015, NYSTEM also awarded Hoffman and Iancu-Rubin an $8-million grant to translate the technology from the laboratory into the clinic, where it is currently in clinical trial.

“Tacitus is committed in its mission to advance next-generation cell therapies with curative potential. Based on our founders’ solid foundation of research, we are translating these discoveries into broad clinical practice as we look to dramatically improve the standard of care for patients with life-threatening conditions,” added Carter Cliff, CEO of Tacitus.