Mechanisms that regulate maintenance of niches for hematopoietic stem cells in aging and cancer.

Life-long production of blood depends on the ability of hematopoietic stem cells (HSCs) to self-renew, differentiate, and form all blood cell lineages. HSCs rely upon a tight interaction with their microenvironment in the bone marrow (also termed the “niche”) to preserve quiescence and maintain normal blood output. These interactions are based upon membrane-bound, locally secreted, and/or long-range signals produced by a complex network of blood vessels, sympathetic nerve fibers, mesenchymal stem cells (MSCs), stromal cells, and hematopoietic cells. Aging of the hematopoietic system is associated with an age-dependent decline in HSC function leading to myeloid cell expansion and a reduction in lymphoid output that contribute to the development of myeloid malignancies. Many advances have been made toward deciphering intrinsic mechanisms that control HSC aging. However, the dependence of HSC dysfunction on the aging microenvironment remains underexplored.

Our interest is to understand mechanisms that control niche aging and contribute to the remodeling of niches that support myeloid malignancy and leukemic stem cells (LSCs). We use rigorous genetic models that target different niche constituents combined with innovative 3D imaging technology to detect endogenous HSC distribution in their native microenvironment. These approaches will provide novel insights into the molecular mechanisms underlying age-dependent stem cell dysfunction and identify factors that can be targeted to develop novel therapies to rejuvenate stem cells niches.

Primary interests of the lab:

Sympathetic nerves and adrenergic signals as regulators of niche homeostasis. Our previous work established that signals from the sympathetic nervous system (SNS) control hematopoietic aging and highlight niche-derived factors as critical regulators of HSC longevity, rejuvenation of which can directly benefit aged stem cells (Maryanovich et al., Nature Medicine 2018). Future efforts are oriented toward identifying targets downstream of the SNS that control niche and HSC aging.

Reactive oxygen species (ROS) role in remodeling niches to support myeloid malignancies and leukemic stem cells (LSCs). Myeloid malignancies elicit alterations to the HSC niche that promote oncogenic expansion and eradication of healthy stem cells. The SNS was shown to be protective against myeloproliferation, as sympathetic denervation or deletion of β- adrenoreceptors accelerated the development of myeloproliferative disease (Hanoun et al., Cell Stem Cell 2014). Our work has shown that SNS signals control homeostasis of niche-derived ROS and that leukemic progression favors high oxidative stress, suggesting that SNS signals may mitigate ROS levels in the BM microenvironment to protect HSC niches during leukemogenesis.

HSC niche metabolism and its role during aging and leukemogenesis. Our goal is to determine how aging and leukemogenesis affect the metabolic activity of niche constituents and perturb their ability to support hematopoiesis. We will investigate the role of the SNS in controlling niche cell metabolism and whether disruption of metabolic activity in the niche can deteriorate both its structure and function to facilitate hematopoietic aging and precondition niches to support leukemic infiltration. We will focus on glucose metabolism, fatty acid metabolism, and mitochondrial oxidative phosphorylation, pathways shown to be critical for stem cell maintenance.

Pinho S, Wei Q, Maryanovich M, Zhang D, Balandrán JC, Pierce H, Nakahara F, Di Staulo A, Bartholdy BA, Xu J, Borger DK, Verma A, Frenette PS. VCAM1 confers innate immune tolerance on haematopoietic and leukaemic stem cells. Nature Cell Biology. 2022 Mar;24(3):290-298

Nakahara F, Borger DK, Wei Q, Pinho S, Maryanovich M, Zahalka AH, Suzuki M, Cruz CD, Wang Z, Xu C, Boulais PE, Ma'ayan A, Greally JM, Frenette PS. Engineering a haematopoietic stem cell niche by revitalizing mesenchymal stromal cells. Nature Cell Biology. 2019 May;21(5):560-567

Maryanovich M, Zahalka AH, Pierce H, Pinho S, Nakahara F, Asada N, Wei Q, Wang X, Ciero P, Xu J, Leftin A, Frenette PS. Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche. Nature Medicine. 2018 May 7; 24:782–791

Maryanovich M, Takeishi S, Frenette PS. Neural Regulation of Bone and Bone Marrow. Cold Spring Harb Perspect Med. 2018 Mar 2. pii: a031344

Zahalka AH, Arnal-Estapé A, Maryanovich M, Nakahara F, Cruz CD, Frenette PS. Adrenergic nerves activate an angio-metabolic switch in prostate cancer. Science. 2017 Oct 20; 358(6361):321-326

Maryanovich M, Zaltsman Y, Ruggiero A, Goldman A, Shachnai L, Zaidman SL, Porat Z, Golan K, Lapidot T, Gross A. A MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate. Nature Communications. 2015 Jul 29; 6:7901

Hanoun M*, Maryanovich M*, Arnal-Estapé A*, Frenette PS. Neural Regulation of hematopoiesis, inflammation and Cancer. Neuron. 2015 Apr 22; 86(2):360-73. Review. (*Co-first author)

Maryanovich M, Gross A. A ROS rheostat for cell fate regulation. Trends in Cell Biology. 2013 Mar; 23(3):129-34

Maryanovich M, Oberkovitz G, Niv H, Vorobiyov L, Zaltsman Y, Brenner O, Lapidot T, Jung S, Gross A. The ATM-BID Pathway regulates quiescence and survival of haematopoietic stem cells. Nature Cell Biology. 2012 Mar 25; 14(5):535-41