A Recipe to Produce Hematopoietic Stem Cells from Embryonic Stem Cells
The hematopoietic cell populations in bone marrow deteriorate with age, negatively affecting the production of immune cells and red blood cells. Given the importance of immune system dysfunction in aging, restoring the hematopoietic populations to youthful competence is thought important. A number of lines of research focus on this goal, one of which is replacement, meaning the delivery of a functional population of hematopoietic stem cells into the bone marrow with the support needed for these cells to survive and engraft. This requires the ability to reliably and cost-effectively generate hematopoietic stem cells from induced pluripotent stem cells made from a tissue sample provided by the recipient. Most of the other capabilities needed to establish this form of therapy exist, but making hematopoietic stem cells remains a challenge. Here, researchers propose a specific approach.
Hematopoietic Stem Cells (HSCs) possess the ability to long-term reconstitute all the blood lineages and generate all blood cell types. As such, the in vitro generation of HSCs remains a central goal in regenerative medicine. Despite many efforts and recent advancements in the field, there is still no robust, reproducible and efficient protocol for generating bona-fide HSCs in vitro. This suggests that certain regulatory elements have yet to be uncovered.
Here, we present a novel and unbiased approach to identifying endogenous components to specify HSCs from pluripotent stem cells. We performed a genome-wide CRISPR activator screening during mesodermal differentiation from mouse embryonic stem cells (mESCs). Following in vitro differentiation, mesodermal KDR+ precursors were transplanted into primary and secondary immunodeficient NSG mice. This approach led to the identification of seven genes (Spata2, Aass, Dctd, Eif4enif1, Guca1a, Eya2, Net1) that, when activated during mesoderm specification, induce the generation of hematopoietic stem and progenitor cells (HSPCs). These cells are capable of serial engraftment and multilineage output (erythroid, myeloid, T lymphoid, and B lymphoid) in vivo.
Single-cell RNA sequencing further revealed that activating these seven genes biases the embryoid bodies towards intraembryonic development, instead of extraembryonic, increasing the number of mesodermal progenitors that can generate HSCs. Our findings underscore the importance of differentiation during the first germ layer specification to generate definitive blood stem cells.
I remember reading in one of Aubrey de Grey's old "recent thesis relevant to aging" about producing loads of invariant natural killer T cells from Hematopoietic stem cells that have been genetically engineered to do so when a small molecule drug is administered. This could be a step towards a more general cancer cure
Also today there was this study proving that clonal expansion of some blood stem cells leads to a loss of diversity with aging and potential sterile sterile inflammation due to an overproduction of myeloid blood cells:
https://www.genengnews.com/topics/omics/blood-aging-revealed-through-a-novel-epigenetic-clonal-tracing-method/
So increasing diversity again could be an "easy" win for increasing health span and lifespan.
"The study also observed that in both older humans and mice, many of the dominant clones show a preference for producing myeloid cells. Previous studies in mice have shown that selectively removing myeloid-biased stem cells can restore a younger profile of blood stem cells, boosting the production of lymphocytes and improving immune responses.
But to study rejuvenation therapies in humans, researchers would first need to identify which clones are problematic, something which has not been possible until now. "If we want to move beyond generic anti-aging treatments and into real precision medicine for aging, this is exactly the kind of tool we need," said Velten. "We can't fix what we can't see and for the first time, EPI-Clone can facilitate this for humans.""