Cód. SSPA: IBiS-C-16
Stem cells reside in a specialized home (microenvironment) which allows them to self-renew, proliferate, differentiate and migrate according to the organism's requirements. Using the blood system as an experimental model, the Microenvironmental physiopathology group investigates the regulation of the microenvironment in physiology and its deregulation in physiopathology.
Purpose
In multicellular organisms, cells do not function in isolation, but in the context of their surrounding microenvironment. In adults, tissue stem cells display the greatest regenerative potential, but can also become the source of cancer, are similarly regulated by a specialized microenvironment. Hematopoietic stem cells (HSCs) can give rise to virtually all blood and immune cells. Our group investigates the extrinsic regulation of HSCs, including their pathological interactions with other cells of the bone marrow (BM) microenvironment, to devise more efficient therapies for hematological malignancies.
Scientific need
Myeloid malignancies, such as myeloproliferative neoplasms (MPNs) and acute myeloid leukemia (AML), are clonal diseases arising in HSCs or hematopoietic progenitor cells, and represent an important medical and societal problem due to their difficulty to treat, costly management and high morbidity and mortality. Myeloid malignancies were previously thought to be driven solely by genetic or epigenetic lesions within hematopoietic cells. However, our group and others have shown that the BM niches which maintain HSCs can act as predisposition events, facilitating mutant HSC survival, uncontrolled expansion, malignancy progression and protection from chemotherapy, ultimately leading to disease recurrence.
Significance
Resembling normal HSCs, mutant HSCs and their progeny depend on their niches for survival, proliferation and resistance to therapy. However, the mechanisms underlying the abnormal interaction of mutant cells with their microenvironment remain largely unknown, despite the fact that they could offer important clues for novel adjuvant therapies to eradicate myeloid malignancies, adding to mutation-directed targeting. Our team investigates and targets specific niche-dependent mechanisms promoting the development, chemoresistance and relapse of myeloid malignancies.
Resarch lines
Our research is focused on the stem cell niche regulation with a translational focus on disease pathogenesis, treatment and regenerative medicine. In particular, we investigate the HSC niche and its targeting for improved management of the myeloid malignancies.
- Hematopoietic stem cell niche
A century ago, hematologists realized that HSCs cannot survive or multiply on their own in the BM, and that they require the support of neighboring cells, the BM stromal cells. These BM stromal cells are connective tissue cells, not blood forming cells, but can also self-renew. There are different types of stromal cells, and one is called mesenchymal stem cell (MSC). MSCs also reside in the BM, and generate cartilage, bone and fat tissue. Our past research found that MSCs are very important in supporting and regulating HSCs. We investigate how MSCs support and regulate normal and (pre)malignant HSCs.
- Hematopoietic stem cell niche regulation
HSCs and some of their derivatives, such as leukocytes, continuously migrate between BM and peripheral circulation. This physiological migration is exacerbated in the clinic: agents that stimulate HSC mobilization allow for non-invasive harvest from peripheral circulation (apheresis), whilst conditioning regimens in the recipient ensure robust BM engraftment upon transplantation. We found that this physiological migration of HSCs and leukocytes is not random or constant, but follows day/night oscillations of autonomic nervous system activity. Therefore, our study found an unexpected connection between the central pacemaker in the brain with the BM HSC niche and suggested ways to increase stem cell yields by selecting the optimal time of apheresis and infusion. This communication is facilitated by the autonomic nervous system, which connects the brain with the periphery. Particularly, the noradrenergic branch of the autonomic nervous system triggers the egress of HSCs and leukocytes from the BM into peripheral circulation, whereas the cholinergic branch promotes BM HSC homing at a different time during day/night cycles.
Our recent research has demonstrated the sympathetic nervous system’s ability to regulate the activity of HSCs in different BM niches7,8. We have traced skeletal cholinergic nerve fibers to a sympathetic origin and have described their bone-anabolic function. Because skeletal cholinergic innervation is also present in humans, these results suggest that the achievement of peak bone mass involves the sympathetic cholinergic system during adolescence and after physical activity. On the hematopoietic side, our results indicate that cholinergic signals preserve HSC quiescence in BM niches near the bone surface. We showed that stress conditions, such as chemotherapy or irradiation, which are routinely used for cancer treatment and conditioning regimens for HSC transplantation (HSCT), increase the signals released by these neurons, which fine tune the control of HSCs by their neighbours (stromal cells). BM cholinergic neural signals increase during stress hematopoiesis and are amplified through other cholinergic cells. As a result, not all HSCs become activated (which could cause their exhaustion), but some remain quiescent, thereby retaining their full potential. Lack of cholinergic innervation impairs balanced responses to chemotherapy or irradiation and reduces HSC quiescence and self-renewal7. These results illustrate the regenerative role of the cholinergic system in bone nature and blood nurture. Together, they suggest that the sympathetic nervous system regulates bone formation and the proliferation of HSCs in separate BM niches and through (seemingly dynamic) changes in neurotransmitter release. This mechanism might serve to adjust bone formation and HSC responses to organismal demands, as a safeguard to prevent stem cell exhaustion during the regeneration process. This mechanism might be important and therapeutically amenable to modulate the recovery of the blood and immune system during regeneration, particularly after HSCT.
- DHematopoietic stem cell niche deregulation in myeloid malignancies
Aging is associated with increased risk of myeloid malignancies. We and others found that the remodelling of BM niches promotes myeloid cell expansion during ageing9. Furthermore, our research found that MPN development is accelerated in an aged BM microenvironment10, suggesting that the specialized niche can modulate mutant cell expansion and might be targetable to prevent malignancy development. Indeed, we found that he interaction of HSCs (carrying the same oncogenic driver) with different BM niches impacts the development of MPNs and and their response to therapy. The mutant HSCs produce an abundance of inflammatory cytokines (and particularly IL1b) that damage nearby Schwann cells protecting sympathetic fibers. This insult, in turn, prevents the nerves from activating other cells that help regulate HSCs (MSCs). This niche damage increases the potential for MPN development11 and might represent a therapeutic target because it fosters the transition from clonal hematopoiesis (very common in the elderly) to MPN12.
An important conclusion from these studies is the different role for the microenvironment (and even the same niche cells) in distinct myeloid malignancies and/or disease stages. One representative example is the two faces of MSCs in AML and MPN: we found that nestin+ niches are reduced in MPN11, but not in AML15. Furthermore, experimental depletion of nestin+ cells accelerated MPN11, but delayed instead AML development15. I, we found that MSCs support AML development and chemoresistance in vivo through a dual mechanism involving increased bioenergetic capacity and anti-oxidant defence and escape from chemotherapy15. Furthermore, BM MSCs supply cap-dependent translation machinery to AML cells via extracellular vesicles, fostering AML relapse. In summary, this research on the BM microenvironment in the myeloid malignancies has identified candidate pathways and molecules17, which will be investigated and targeted in the future.
- Hematopoietic stem cell transplantation
HSCT remains the only cure for many cancers or inherited metabolic or immune disorders. However, it can be very toxic, and relatively few patients can benefit from this treatment. HSCT requires enough functional stem cells, which need to find a suitable home in the recipient. The demand for HSCT will continue at the existing rate, despite the onset of novel gene therapy approaches. However, important unmet needs remain, particularly in the context of HSCT for leukemia treatment: 1) up to half of the leukemias re-emerge after transplantation from malignant cells that are resistant to current therapies; 2) another problem is that the BM HSC niche is not acceptive in some recipients, reducing the number of eligible patients; 3) last (but not least), others develop a reaction of the graft against their own body (graft vs host disease). Therefore, the main goals of our research program are: 1) to eradicate leukemic cells to avoid tumor re-occurrence through HSC niche-targeted therapies, which are developed in the lab, and subsequently tested in clinical trials; 2) to achieve efficient stem cell engraftment and blood regeneration through interventions that improve the HSC niche when it’s needed; 3) a third goal is to reduce the risk of slow blood regeneration or the development of graft vs host disease, building on candidate functional biomarkers that may allow to improve donor selection and decrease excessive inflammation after transplantation.
