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Chemotherapy and radiation are common treatments for many
They are powerful treatments in terms of destroying rapidly
dividing cancer cells, but cannot distinguish between cancerous and
non-cancerous cells, such as hematopoietic stem cells (HSCs). This means
healthy cells are destroyed in the process of fighting off the cancer cells.
HSCs are the origin of blood and immune cells, which in turn
are responsible for fighting infection. Thus, it is common for patients
undergoing high doses of radiation and chemotherapy to have compromised immune
HSC transplantation replaces healthy cells, and is a
promising avenue for reconstituting proper hematopoietic functioning to effectively
rebuild the immune system after chemotherapy.
Hematopoietic stem cell transplantation success is measured
by acceptance of donor tissue or cells (graft) as well as time to engraftment (immune
reconstitution). One of the major factors in determining success of immune
reconstitution is the number of CD34+ cells in the graft prior to
Bone marrow and peripheral blood-derived HSCs allow for
large numbers of CD34+ cells to be harvested and transplanted, but they are of
limited utility if an HLA-matched donor is unavailable. Cord blood-derived
hematopoietic stem cells offer a potential solution, as the cells tend to be
more naïve, which may lead to fewer occurrences of host-versus-graft-disease
(GVHD) in instances of HLA-mismatch.
Despite their potential in combating GVHD, cord
blood-derived HSCs also pose a major challenge due to the limited number of
cells available from any particular donor. Thus, many research labs and
clinical trials are currently focused on developing methods for ex-vivo expansion of cord blood-derived HSCs.
One of the earliest efforts of ex-vivo expansion was focused on culture with exogenous cytokines. However,
early clinical trials indicated only a moderate increase in CD34+ cells and no benefit
in terms of time to immune reconstitution.
Due to the limited clinical efficacy of culture with
exogenous cytokines, efforts have begun to shift toward understanding and
controlling the various cell-cell interactions and molecular pathways involved
in cell-fate decisions. Two promising methods are co-culture with bone marrow
stromal cells and Notch signaling.
The hematopoietic micro-environment, or bone marrow niche,
is comprised of many bone marrow stromal cell types that work together to help
control HSC self-renewal, proliferation, and differentiation. These include mesenchymal
stem cells (MSCs), endothelial cells, CXCL12-abundant reticular (CAR) cells,
osteoblast lineage cells and Schwann cells, which influence hematopoietic stem
cell self-renewal through secretion of cytokines as well as cell-cell
The below figure illustrates the influence of cytokine
expressing bone marrow stromal cells on HSC self-renewal. MSCs, endothelial
cells, and CAR cells all express CXC12 (SD-1), SCF, and angiopoietin.
Osteoblast lineage cells express CXCL12 and TPO, whereas Schwann cells express
the active form of TGF-β.
There are currently research efforts aimed at exploiting the
cell-cell interactions of the bone marrow niche to facilitate ex-vivo expansion of HSCs. Techniques
include co-culture of HSCs with bone marrow stromal cells and addition of
supporting exogenous cytokines, which has shown a 40-fold increase of CD34+
cells. In addition, there are clinical trials in progress to assess the safety
and efficacy of transplantation of ex-vivo
co-culture expanded HSCs.
Co-culture with bone marrow stromal cells likely involves
many signaling pathways and cell-cell interactions, which may prove difficult
to reproducibly control. A somewhat more defined attempt of exploiting HSC
self-renewal is focused on the more specific Notch signaling pathway.
The below image is adapted from a publication by Dahlberg et al. and proposes a mechanism whereby Notch2
influences HSC self-renewal and differentiation by first blocking HSC
progression toward multipotent progenitors (MPP). Notch 2 can then further
block MPPs from differentiation to lymphocytic B cells and to myeloid lineage
cells. Conversely, Notch1 promotes differentiation of MPPs to lymphocytic T
Dahlberg et al. were
able to initiate HSC self-renewal by activating Notch2 signaling through the
use of immobilized Delta1 (Notch2 ligand), fibronectin, and cytokines to both
block progression toward MPPs as well as promote HSC self-renewal. This method has
been tested in a Phase I clinical trial, with promising results.
These two examples help to illustrate the impressive
progress in our collective understanding of the molecular mechanisms involved
in the in-vitro expansion of HSCs.
However, there is still more to discover before we can fully realize the
potential that stem cell based therapies can provide.
Lonza is committed to supporting your efforts in stem cell
therapy research, which is why we offer both research
grade cord blood-derived CD34+ cells as well as cell
therapy tissue acquisition capabilities. Please contact Scientific
Support for more information about our research use, cord blood-derived
1. Regulation of hematopoietic stem cells by bone marrow stromal cells. http://www.ncbi.nlm.nih.gov/pubmed/24210164
2. Ex vivo expansion of human hematopoietic stem and progenitor cells. http://www.ncbi.nlm.nih.gov/pubmed/21436068
3. Concise review: ex vivo expansion of cord blood-derived hematopoietic stem and progenitor cells: basic principles, experimental approaches, and impact in regenerative medicine. http://www.ncbi.nlm.nih.gov/pubmed/24101670
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