CD34+ Haematopoietic (adult) stem cells (HSCs) as fundamental reagents in preclinical research

Phase contrast microscopy images of Human CD34+ Haematopoietic stem cells isolated from umbilical cord (left) and mobilised peripheral blood (right)
Lakshman Varanasi, PhD, Science Associate    September 28, 2020

Haematopoietic stem cells (HSCs) give rise to all the lymphohaematopoietic lineages present in the blood i.e. are progenitors of the cellular component of blood. This includes red blood cells, lymphocytes, monocytes, macrophages, neutrophils, basophils, eosinophils, and platelets. The HSCs reside in the bone marrow, and (in new-born infants) in the umbilical cord. They comprise a small percentage (approx. 1.5%) of the marrow cells but may be collected by “flushing” with G-CSF (Neupogen®), or Mozobil®, or both; the chemicals roust out these cells from the marrow and into the peripheral blood, a process called mobilization. Bone marrow cells/ HSCs maybe then collected from mobilized peripheral blood (PB) by leukapheresis; the collected cell set is called a Leukopak. Needless to mention, the entire collection process is closely monitored to ensure the donor and recipient’s safety. The HSCs are recognised by a phosphoglycoprotein cell surface marker protein called CD34, known to enable proliferation and inhibit differentiation, and to enable T-lymphocytes (or T-cells) to attach to endothelia. This marker is peculiar to the HSCs and their lineages, although it is now believed that it may occur in other cell types as well.

HSCs are fundamental reagents in preclinical research. Their multilineage potential renders HSCs ideal reagents for a variety of preclinical research applications. These include hematotoxicity and pyrogenicity tests, and as grafts for the creation of humanised mice (humice). The last is a relatively new concept and has quickly found application in studies of immunology, immuno-oncology, blood-related conditions(for instance, aberrant Haematopoiesis, Anaemia, Thalassemia and Haemophilia), and infectious diseases. The severely immunodeficient (or nude) mice engrafted with human HSCs have lymphocytes of human origin, while other blood cells are chimeric, i.e. of murine and human origin. The system, therefore, simulates closely the human immune system; infectious disease and the attendant immune/inflammatory response can be most closely modelled in it; for instance, the CD8 Lymphocytes from the CD34+ progenitor cells are fully responsive to a vaccine. The system allows for (pre-clinical) testing that can generate predictive data rapidly and at cost before the study is advanced to human clinical trials. It can inform and guide human trials, if not eliminate them altogether. The model system holds promise for scientists and businesses alike, and the market for humanized mouse models has expanded commensurately.

HSCs’ are a versatile platform, and are not restricted to the said/above in vivo application. They can also be used in vitro for screening, efficacy, or toxicity testing, or a combination of these. Chemotherapeutic drugs that suppress the growth of cancers in an individual, also suppress the haematopoietic system at the levels they are administered; the cytotoxicity (or other effects) of a compound on haematopoietic cells in vitro is an important indicator of its suitability as a chemotherapeutic drug, and this is generally applicable to any investigational new drug candidate.

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