Looking Back and Looking Ahead
Looking Back and Looking Ahead

ADRCs- "Looking back and Looking ahead"


The Adipose-derived Stem Cell: Looking Back and Looking Ahead- Dr. Patricia Zuk

In 2002, researchers at UCLA published a manuscript in Molecular Biology of the Cell describing a novel adult stem cell population isolated from adipose tissue—the adipose-derived stem cell (ASC).
Since that time, the ASC has gone on to be one of the most popular adult stem cell populations currently being used in the stem cell field. With multilineage mesodermal potential and possible ectodermal and endodermal potentials also, the ASC could conceivably be an alternate to pluripotent ES cells in both the lab and in the clinic. In this retrospective article, a historical perspective on the ASC is given together with exciting new applications for the stem cell being considered today.
Until the year 2000, adult stem cell articles seemed to be limited to the HSC, the MSC, the NSC (neural stem cell) and the muscle satellite cell. However, 2001 saw the addition of another adult stem cell to the roster: the adipose-derived stem cell (ASC).
In the journal Tissue Engineering our team first used the term processed lipoaspirate (PLA) cells, owing to their isolation from human lipoaspirates, and proposed that the ASC was a multilineage stem cell population that could be isolated from the stromo-vascular fraction of adipose tissue (Zuk et al., 2001).
Why adipose tissue would contain a stem cell population is not that far-fetched. The conversion of adipose tissue to calcified bone has been observed in several diseases including lupus, subcutaneous fat necrosis (Shackelford et al., 1975) and Paget’s disease (Clarke and Williams, 1975). This conversion should not be possible by the resident, unipotent pre-adipocyte precursor population. Also, adipose tissue is derived from the embryologic mesenchyme and possesses a well-described stroma that like bone marrow could feasibly contain a mesenchymal stem cell population.

The initial results published in Tissue Engineering seemed to support this theory. To confirm this theory, our team undertook a more extensive molecular and biochemical analysis of the ASC (i.e., the PLA cell) in our 2002 MBoC article (Zuk et al., 2002). This article not only confirmed our earlier work that the ASC is capable of differentiating into multiple mesodermal cell types—adipogenic, chondrogenic, osteogenic, and myogenic (Zuk et al., 2001), but utilized additional approaches such as the expression of multiple lineage–specific genes and functional biochemical assays to confirm this property. Combining these approaches, the data of our MBoC article appeared to fulfill one important requirement of a stem cell: differentiation capacity. However, the MBoC article also fulfilled another important requirement specific to adult stem cells, that of clonogenicity. One of the most obvious hurdles for adult stem cell identification is the heterogeneity of their origin tissue. Because of this, the observed multilineage differentiation by ASCs may simply be due to the presence of multiple precursor populations, each completing their development. One way to circumvent this would be the isolation of a stem cell, combined with proof of its multipotency.
Therefore, the 2002 MBoC article also contained data confirming multilineage differentiation of single ASC clones. Having demonstrated differentiation capacity and clonogencity, we felt confident that the ASC was, in fact, a new adult stem cell population and, since 2002, many groups have confirmed our proposal in both human and animal ASC populations. The ability of both human and animal ASCs to undergo mesodermal differentiation at the in vivo level has also been presented using a wide variety of animal model systems, but what has become more exciting is the potential of ASCs beyond the mesodermal lineage. Our original MBoC article suggested that ASCs might possess the ability to differentiate to neuronal-like cells of the ectodermal lineage. Confirmatory studies examining this capacity quickly followed (Safford et al., 2002; Ashjian, 2003). Today, the ability of ASCs to form cells consistent with neurons (Kang et al., 2004), stem-cell-therapyoligodendrocytes (Safford et al., 2004), functional Schwann cells (Kingham et al., 2007; Xu et al., 2008), and cells of the epidermal lineage (Trottier et al., 2008) have added credence to the theory that ASCs may be pluripotent rather than multipotent. Not surprisingly, studies describing the endodermal differentiation of ASCs have also appeared, with ASCs being induced to form hepatocytes and pancreatic islets (Seo et al., 2005; Timper et al., 2006). The theory that ASCs, like ES cells, may be pluripotent and capable of forming multiple cell types within all three germ layers was proposed.


The possibility that the ASC is pluripotent would obviously revolutionize the stem cell field. Why bother with the ethical and political difficulties of the ES cell when a plentiful source of similarly potent stem cells could be found in your fat? However, we have a long way to go with the ASC before such a statement should be seriously considered.
Fortunately, researchers around the world consider the ASC exciting enough to make it the focus of their work. Today, a search of PubMed using the terms “adipose” and “stem cell” yields over 2000 entries, making the ASC one of the most popular adult stem cells currently being explored today. Today, the proposed uses for ASCs in tissue repair/regeneration are quite impressive. Hot areas of research include ischemia revascularization, cardiovascular tissue regeneration, bone/cartilage repair, and urinary tract reconstruction With its mesodermal origin, the application of ASCs to bone and cartilage defects is obvious along with their use in tendon and intervertebral disk repair
However, the use of ASCs is expanding to both the ectodermal and endodermal lineages. Work by di Summa et al. (2009) has suggested that rat ASCs may stimulate peripheral nerve repair, whereas Ryu et al. (2009) has observed functional recovery upon their transplantation into dogs with acute spinal cord damage. Liver injury repair may also be possible with transplantation of rat ASCs, decreasing key liver enzyme levels and increasing serum albumin (Liang et al., 2009). Even diabetes may be a target for ASC therapy, with murine ASCs reducing hyperglycemia in diabetic mice (Kajiyama et al., 2010). Most recently, researchers have begun to explore the potential uses of “reprogrammed” ASCs as iPS (induced pluripotent stem) cells and have suggested that the ASC may be easier to reprogram than the fibroblast (Sun et al., 2009).
However, researchers are also beginning to “think outside the box.” The transplantation of human ASCs into a murine model of Huntington’s appears to slow progression of the disease, inducing the expression of neuroprotective genes by the host (Lee et al., 2009). Human ASCs have recently been used to deliver myxoma virus to experimental gliomas in nude mice, making the ASC a possible vector for oncolytic viral treatment of brain tumors (Josiah et al., 2009). Human ASCs engineered to convert 5-fluorocytosine to the antitumor drug 5-fluorouracil have also been used to inhibit prostatic tumor growth. Finally, the ability of ASCs to suppress specific aspects of the immune system (Puissant et al., 2005) has created another exciting research avenue encompassing everything from organ antirejection to the amelioration of autoimmune diseases (Gonzalez et al., 2009; Riordan et al., 2009).
Nothing seems to be out of the realm of possibility, with work by Park and colleagues investigating whether the secretory products from ASCs can act as antiwrinkle agents, promoting dermal thickness (Kim et al., 2009). Even the popular topic of erectile dysfunction may be solved with the transplantation of ASCs (Lin et al., 2009a)! What might be more exciting is the application of ASC in our clinics. Although the excitement regarding the ES cell has picked up with the Obama administration’s approving an increase in the number of new ES lines and a limited human clinical trial, what many people don’t realize is that the ES cell has yet to treat any disease.
This in contrast to the HSC, which has been utilized successfully in medicine for the last four decades! On the zukpatriciabasis of this, many researchers firmly believe that the adult stem cell might be more useful clinically useful than the ES cell. In support of this, there are emerging clinical applications of the ASC, which started in 2004 with the combination of ASCs and bone grafts to treat extensive craniofacial damage in a 7-year-old girl (Lendeckel et al., 2004) to a recently completed stage II clinical trial for Crohn’s disease (Garcia-Olmo et al., 2009). ASCs have also been applied in trials for urinary incontinence (Yamamoto et al., 2009) and graft versus host disease (Fang et al., 2007).


Looking back, the isolation of the ASC seemed to preface a decade that could easily be named the “decade of the adult stem cell,” with an impressive number of groundbreaking articles describing the isolation of adult stem cells not only from adipose tissue but from skin, liver, digestive epithelium, pancreas, and neural crest.
Even tissues as unexpected as amniotic fluid, dental pulp, hair follicles, and eyelids have all been found to contain resident stem cell populations. However, the ASC does have one important advantage over these other sources—availability. There is no human tissue as expendable as adipose tissue, making it relatively easy to isolate adequate numbers of ASCs for possible human therapies.
With this fact, together with the early clinical uses of ASCs that report no adverse effects, it would seem only a matter of time before more and more clinical applications of ASCs are reported. Although the ES cell with its proven self-renewal capacity and pluripotency would seem to be a more appropriate stem cell to use clinically, the recent work on ASCs would suggest that this adult stem cell may prove to be an equally powerful weapon in the treatment of  human disease and injury

Only time will tell.

Editors note: The team around Dr.Zuk was instrumental in describing Fat cells , which obviously was very important in spreading the news amongst academia. As Dr. Zuk describes at the end of the paper, stem cells now have been found in all kinds of tissue types- understanding why that is, we owe to Dr. Arnold Caplan, the first scientist to describe the MSC (not its discoverer). Of course- Caplan and his papers are an impotant part of this website too. But first- Dr. Zuk´s monumental paper from 2002 is a free paper available on PubMed-  for that reason I provide an overview of all six available free papers below.

pubmed: zuk, patricia

23 February 2019

NCBI: db=pubmed; Term=Zuk, Patricia AND (free full text[sb])
  • Manual isolation of adipose-derived stem cells from human lipoaspirates.
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    Manual isolation of adipose-derived stem cells from human lipoaspirates.

    J Vis Exp. 2013;(79):e50585

    Authors: Zhu M, Heydarkhan-Hagvall S, Hedrick M, Benhaim P, Zuk P

    In 2001, researchers at the University of California, Los Angeles, described the isolation of a new population of adult stem cells from liposuctioned adipose tissue that they initially termed Processed Lipoaspirate Cells or PLA cells. Since then, these stem cells have been renamed as Adipose-derived Stem Cells or ASCs and have gone on to become one of the most popular adult stem cells populations in the fields of stem cell research and regenerative medicine. Thousands of articles now describe the use of ASCs in a variety of regenerative animal models, including bone regeneration, peripheral nerve repair and cardiovascular engineering. Recent articles have begun to describe the myriad of uses for ASCs in the clinic. The protocol shown in this article outlines the basic procedure for manually and enzymatically isolating ASCs from large amounts of lipoaspirates obtained from cosmetic procedures. This protocol can easily be scaled up or down to accommodate the volume of lipoaspirate and can be adapted to isolate ASCs from fat tissue obtained through abdominoplasties and other similar procedures.

    PMID: 24121366 [PubMed - indexed for MEDLINE]

  • Nuclear fusion-independent smooth muscle differentiation of human adipose-derived stem cells induced by a smooth muscle environment.
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    Nuclear fusion-independent smooth muscle differentiation of human adipose-derived stem cells induced by a smooth muscle environment.

    Stem Cells. 2012 Mar;30(3):481-90

    Authors: Zhang R, Jack GS, Rao N, Zuk P, Ignarro LJ, Wu B, Rodríguez LV

    Human adipose-derived stem cells hASC have been isolated and were shown to have multilineage differentiation capacity. Although both plasticity and cell fusion have been suggested as mechanisms for cell differentiation in vivo, the effect of the local in vivo environment on the differentiation of adipose-derived stem cells has not been evaluated. We previously reported the in vitro capacity of smooth muscle differentiation of these cells. In this study, we evaluate the effect of an in vivo smooth muscle environment in the differentiation of hASC. We studied this by two experimental designs: (a) in vivo evaluation of smooth muscle differentiation of hASC injected into a smooth muscle environment and (b) in vitro evaluation of smooth muscle differentiation capacity of hASC exposed to bladder smooth muscle cells. Our results indicate a time-dependent differentiation of hASC into mature smooth muscle cells when these cells are injected into the smooth musculature of the urinary bladder. Similar findings were seen when the cells were cocultured in vitro with primary bladder smooth muscle cells. Chromosomal analysis demonstrated that microenvironment cues rather than nuclear fusion are responsible for this differentiation. We conclude that cell plasticity is present in hASCs, and their differentiation is accomplished in the absence of nuclear fusion.

    PMID: 22213158 [PubMed - indexed for MEDLINE]

  • Osteoblast interactions within a biomimetic apatite microenvironment.
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    Osteoblast interactions within a biomimetic apatite microenvironment.

    Ann Biomed Eng. 2011 Apr;39(4):1186-200

    Authors: Tsang EJ, Arakawa CK, Zuk PA, Wu BM

    Numerous reports have shown that accelerated apatites can mediate osteoblastic differentiation in vitro and bone formation in vivo. However, how cells interact within the apatite microenvironment remains largely unclear, despite the vast literature available today. In response, this study evaluates the in vitro interactions of a well-characterized osteoblast cell line (MC3T3-E1) with the apatite microenvironment. Specifically, cell attachment, spreading, and viability were evaluated in the presence and absence of serum proteins. Proteins were found to be critical in the mediation of cell-apatite interactions, as adherence of MC3T3-E1 cells to apatite surfaces without protein coatings resulted in significant levels of cell death within 24 h in serum-free media. In the absence of protein-apatite interaction, cell viability could be "rescued" upon treatment of MC3T3-E1 cells with inhibitors to phosphate (PO(4) (3-)) transport, suggesting that PO(4) (3-) uptake may play a role in viability. In contrast, rescue was not observed upon treatment with calcium (Ca(2+)) channel inhibitors. Interestingly, a rapid "pull-down" of extracellular Ca(2+) and PO(4) (3-) ions onto the apatite surface could be measured upon the incubation of apatites with α-MEM, suggesting that cells may be subject to changing levels of Ca(2+) and PO(4) (3-) within their microenvironment. Therefore, the biomimetic apatite surface may significantly alter the microenvironment of adherent osteoblasts and, as such, be capable of affecting both cell survival and differentiation.

    PMID: 21234689 [PubMed - indexed for MEDLINE]

  • The adipose-derived stem cell: looking back and looking ahead.
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    The adipose-derived stem cell: looking back and looking ahead.

    Mol Biol Cell. 2010 Jun 1;21(11):1783-7

    Authors: Zuk PA

    In 2002, researchers at UCLA published a manuscript in Molecular Biology of the Cell describing a novel adult stem cell population isolated from adipose tissue-the adipose-derived stem cell (ASC). Since that time, the ASC has gone on to be one of the most popular adult stem cell populations currently being used in the stem cell field. With multilineage mesodermal potential and possible ectodermal and endodermal potentials also, the ASC could conceivably be an alternate to pluripotent ES cells in both the lab and in the clinic. In this retrospective article, a historical perspective on the ASC is given together with exciting new applications for the stem cell being considered today.

    PMID: 20375149 [PubMed - indexed for MEDLINE]

  • Bone induction by BMP-2 transduced stem cells derived from human fat.
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    Bone induction by BMP-2 transduced stem cells derived from human fat.

    J Orthop Res. 2003 Jul;21(4):622-9

    Authors: Dragoo JL, Choi JY, Lieberman JR, Huang J, Zuk PA, Zhang J, Hedrick MH, Benhaim P

    PURPOSE: We have isolated pluripotent mesenchymal progenitor cells in large numbers from liposuction aspirates (processed lipoaspirate cells or PLAs). This study examines the osteogenic potential of PLAs and bone marrow aspirate cells (BMAs), when exposed to either recombinant human bone morphogenetic protein (BMP)-2 (rh-BMP-2) or adenovirus containing BMP-2 cDNA (Ad-BMP-2).
    METHODS: Liposuction aspirates underwent proteolytic digestion to obtain PLAs. After exposure to exogenous rh-BMP-2 or Ad-BMP-2 for four or seven days, PLAs and BMAs were assessed by histochemistry, spectrophotometry and RT-PCR. Western blotting and ELISA confirmed BMP gene transduction. Results were compared to osteoblasts and cells in osteogenic media only. PLA-Ad-BMP-2 cells were seeded on matrices and implanted in the hind limbs of SCID mice.
    RESULTS: Analysis of quantified bone precursor assays including extracellular ALP histomorphometry, intracellular ALP spectrophotometry, and calcified extracellular matrix (von Kossa) histomorphometry revealed that PLAs treated with exogenous rh-BMP-2 or transduced with a BMP-2 containing adenovirus (PLA-Ad-BMP-2) produced more bone precursors than osteoblasts (p=0.001). PLAs treated with exogenous rh-BMP-2 or PLA-Ad-BMP-2 also produced more bone precursors than BMAs (p=0.001), except for day 7 ALP histomorphometry (p=0.343). ELISA confirmed successful BMP-2 production by both progenitor cell groups transduced with Ad-BMP-2. H&E sections from collagen I matrices seeded with PLA-Ad-BMP-2 cells confirmed bone formation at six weeks.
    CONCLUSIONS: Liposuction aspirates contain PLAs that can be transfected with the BMP-2 gene, with rapid induction into the osteoblast phenotype at a rate comparable to rh-BMP-2 and osteoblast groups. Transduced PLAs produce more bone precursors with faster onset of calcified extracellular matrix than transduced BMAs. PLAs may be an ideal source of mesenchyme-lineage stem cells for gene therapy and tissue engineering.

    PMID: 12798061 [PubMed - indexed for MEDLINE]

  • Human adipose tissue is a source of multipotent stem cells.
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    Human adipose tissue is a source of multipotent stem cells.

    Mol Biol Cell. 2002 Dec;13(12):4279-95

    Authors: Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH

    Much of the work conducted on adult stem cells has focused on mesenchymal stem cells (MSCs) found within the bone marrow stroma. Adipose tissue, like bone marrow, is derived from the embryonic mesenchyme and contains a stroma that is easily isolated. Preliminary studies have recently identified a putative stem cell population within the adipose stromal compartment. This cell population, termed processed lipoaspirate (PLA) cells, can be isolated from human lipoaspirates and, like MSCs, differentiate toward the osteogenic, adipogenic, myogenic, and chondrogenic lineages. To confirm whether adipose tissue contains stem cells, the PLA population and multiple clonal isolates were analyzed using several molecular and biochemical approaches. PLA cells expressed multiple CD marker antigens similar to those observed on MSCs. Mesodermal lineage induction of PLA cells and clones resulted in the expression of multiple lineage-specific genes and proteins. Furthermore, biochemical analysis also confirmed lineage-specific activity. In addition to mesodermal capacity, PLA cells and clones differentiated into putative neurogenic cells, exhibiting a neuronal-like morphology and expressing several proteins consistent with the neuronal phenotype. Finally, PLA cells exhibited unique characteristics distinct from those seen in MSCs, including differences in CD marker profile and gene expression.

    PMID: 12475952 [PubMed - indexed for MEDLINE]

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This is attracting plastic surgeons and other under qualified clinics to dabble in the regenerative medicine.

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