- Professor of Medicine (in Microbiology and Immunology)
The overarching focus of the Snoeck laboratory is translational stem cell research, and consists of two major vignettes: hematopoietic stem cells (HSCs), the historical focus of the lab, and a more recently developed project on lung development from human pluripotent stem cells (hPSCs).
I. Human lung development and disease modeling
The respiratory system arises from buds on the ventral anterior foregut endoderm (AFE) that undergo a stereotyped branching process followed by specialization of the airway epithelium in the stalks while, distally, alveoli develop where gas exchange will take place. We have published a strategy to achieve the generation of developmental lung progenitors from hPSCs. These were capable of further differentiation into airway and, predominantly, distal lung cells in 2D cultures. Recapitulation of lung development from human pluripotent stem cells (hPSCs) in three dimensions (3D) would allow innovative strategies for disease modeling, drug discovery and regenerative medicine. We developed two culture systems in 3D, that are used to study viral pathogenesis and fibrotic lung disease, with a focus on idiopathic pulmonary fibrosis (IPF).
IPF is an intractable lung disease with a median survival of 3-4 years. 30-40,000 Americans die from this disease each year. As currently no curative treatments are available except for lung transplantation, innovative approaches are urgently needed. Developing such approaches requires insight into pathogenesis. The nature of some predisposing mutations strongly suggests a key role for dysfunction of surfactant-producing type II alveolar epithelial (ATII) cells. Our lung organoid model allowed recapitulation of fibrosis in hPSCs with engineered mutations (Hermansky-Pudlak Syndrome 1, 2 and 4) that predispose with high penetrance to IPF, thus allowing investigation of pathogenesis and eventually establishment of drug screens.
A second endeavor is the generation of engraftable, multipotential lung and airway progenitors. Several lung diseases would theoretically be amenable to stem cell therapies. These include a fraction of patients with cystic fibrosis (CF) that does not respond sufficiently to currently available corrector and potentiator drugs, infants with respiratory failure caused by surfactant deficiencies and victims of severe inhalation injury. However, engraftment of progenitor cells in the lung remains a challenge because neither an expandable progenitor population with engraftment potential nor an appropriate conditioning regimen of the recipient have been identified. To address the first challenge, we have developed a strategy isolate and expand putative human fetal lung progenitors from 3D organoids derived from human pluripotent stem cells which can engraft distal lung of in experimental animal models.
Green M, Chen A, Nostro MC, d’Souza S, Schaniel C, Lemischka IR, Gouon-Evans V, Keller G, Snoeck HW. (2011). Generation of anterior foregut endoderm from human embryonic and induced pluripotent stem cells. Nat. Biotechnol., 29:267-272.
Huang SX, Islam MN, O’Neill J, Hu Z, Yang Y-Y, Chen Y-W, Green MD, Mumau M, Vunjac-Novakovic G, Bhattacharya J, Snoeck HW. (2014) Highly efficient generation of lung and airway epithelial cells from human pluripotent stem cells. Nat Biotechnol., 32:84-91.
Huang SX, Green M, Toste A, Mumau M, Chen YW, Snoeck HW (2015) Protocol of for the generation of lung and airway epithelial cells from human pluripotent stem cells. Nat. Protocols, 10:413-425.
Ciancanelli M, Huang SX, Luthra P, Garner H, ITan Y, Volpi S, Trouillet C, Schmolke M, Isrealsson E, Herman M, Hermesh T, Lorenzo L, Albrecht RA, Leung LW, Okada S, Picard C, Ringuier B, Troussier F, Chaussabel D, Abel L, Pellier I, Notarangelo LD, Garcia-Sastre A, Basler CF, Geissmann F, Zhang SY, Snoeck HW, Casanova JL (2015) Impaired innate and intrinsic IFNα/β amplification underlies life-threatening influenza in human inherited IRF7 deficiency. Science, 348:448-553.
Chen YW, Huang SX, Rodrigues Toste de Carvalho AL, Ho SH, Islam MS, Volpi S, Notarangelo LS, Ciancanelli M, Casanova LS, Bhattacharya J, Liang AF, Palermo LM, Porotto M, Moscona A, Snoeck HW. (2017) A three-dimensional model of human lung development and disease from pluripotent stem cells. Nat Cell Biol., 19:542-549.
Toste de Carvalho, AL, Liu HY, Strikoudis A, Dantas TJ, Chen YW, Vallee RB, Correia-Pinto J, Snoeck HW. (2019) Glycogen Synthase Kinase 3 induces multilineage maturation of lung progenitors derived from human pluripotent stem cells in 3D culture. Development, Jan 22;146(2).
Strikoudis A, Cieslak A, Loffredo L, Chen YC, Patel N, Saqi A, Lederer DJ, Snoeck HW. (2019). Modeling of fibrotic lung disease using 3D organoids derived from human pluripotent stem cells. Cell Reports, 27(12):3709-3723.e5.
De Carvalho AL, Liu HY, Chen, YW, Porotto M, Moscona A, Snoeck HW. (2021). The in vitro multi-lineage differentiation and maturation of lung and airway cells from human pluripotent stem cell-derived lung progenitors in 3D. Nat Protoc:1802-1829.
Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) and have the unique capacity to self-renew and to differentiate, generating all blood lineages throughout life or in a patient after transplantation. HSCs are therefore not only paradigmatic stem cells, but are also used for stem cell therapies for a wide range of hematological diseases. Despite significant progress in our understanding of the biological mechanisms regulating HSC features such as self-renewal, differentiation and quiescence, a coherent understanding of how these mechanisms act in concert to regulate HSCs homeostasis has not emerged yet, and maintenance of HSCs in vitro remains challenging. The mechanisms underlying aging of HSCs are also unclear, although these age-related changes, expansion of the HSC compartment and loss of lymphoid potential, are very likely implicated in age-associated clonal hematopoiesis, myeloid malignancies and immune dysfunction. Understanding these mechanism will have major translational relevance. One organelle of which role and function in HSCs is unclear is the mitochondrion. A relation between mitochondrial dysfunction and aging has been long suspected, but dissecting its details remains as a major challenge for aging research. Our lab showed that mitochondrial turnover, dynamics and calcium handling are regulated in an exceptional fashion in HSCs compared to other cell types, and strongly impacts their function. HSCs can be maintained in vitro in a low-calcium environment, an environment we found is also encountered in the bone marrow. Furthermore, we found that mitochondrial dynamics profoundly affect cell fate and aging of HSCs. It hoped that further studies along these lines will lead to physiological approaches to maintain, expand and manipulate HSCs in vitro.
Avagyan S, Aguilo F, Kamezaki K, Snoeck HW (2011). Quantitative trait mapping reveals a regulatory axis involving peroxisome proliferator-activated receptors, PRDM16, transforming growth factor-?2 and FLT3 in hematopoiesis. Blood, 118:6078-6086.
Aguilo F, Avagyan S, Labar A, Sevilla A, Lee DF, Kumar P, Lemischka IR, Zhou BY, Snoeck HW. (2011). Prdm16 is a physiological regulator of hematopoietic stem cells. Blood, 117:267-272.
Snoeck HW (2015) Can Metabolic Mechanisms of Stem Cell Maintenance Explain Aging and the Immortal Germline? Cell Stem Cell 16:528-584.
Luchsinger LL, Justino de Almeida M, Corrigan DJ, Mumau M, Snoeck HW (2016). Mitofusin 2 maintains hematopoietic stem cells with extensive lymphoid potential. Nature, 529(7587):528-531.
Justino M, Luchsinger LL, Williams L, Snoeck HW (2017). Elevated mitochondrial mass in hematopoietic stem cells. Cell Stem Cell 21:725-729.
Snoeck HW (2017). Mitochondrial regulation of hematopoietic stem cells. Curr Opin Cell Biol, 49:91-99.
Corrigan DJ, Luchsinger LL, Williams LJ, de Almeida MJ, Strikoudis A, Snoeck HW (2018). PRDM16 isoforms differentially regulate normal and leukemic hematopoiesis and inflammatory gene signature. J Clin Invest, 128:3250-3264.
Luchsinger LL, Strikoudis A, Danzl NM, Bush EC, Finlayson MO, Satwani P, Sykes M, Snoeck HW. (2019). Harnessing hematopoietic stem cell low intracellular calcium improves their maintenance in vitro. Cell Stem Cell, 25:225-240.
Departments and Divisions
- Department of Medicine
Centers / Institutes / Programs
- Herbert Irving Comprehensive Cancer Center
- Ya-Wen Chen, PhD,
- Linda Williams,
- Larry Luchsinger, PhD,
- Rafael Gras, PhD,
- Sarah Huang, PhD,
- Mariana Almeida,
- David Corrigan,
- Melanie Mumau,
- Ana Rodrigues,